literature review on stem cells

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Literature review on stem cells top presentation writers services for masters

Literature review on stem cells

Differentiation potential and the mesengenic process modified from Servier Medical Art, licensed under a Creative Common Attribution 3. Regarding differentiation into the adipogenic lineage, supplementation includes dexamethasone, indomethacin, insulin, and isobutylmethylxanthine. The differentiation into these three lineages is evaluated as for the presence of fat droplets adipogenesis , proteoglycans and type II collagen synthesis chondrogenesis , or mineralization of calcium deposits and increase in alkaline phosphatase expression osteogenesis Sami et al.

MSCs can differentiate into other lineages, such as the neurogenic, myogenic, tenogenic, and others as it was previously reported by several research groups Branquinho et al. For instance, a process defined as mesengenesis has been reported by Caplan , where MSCs originated myoblasts, ligaments, tendons and other cell types Sami et al.

Ever since, MSCs have been reported to originate cells from the heart, peripheral blood, cord blood, muscle, AT, lung, trabecular bone, intestine, kidney, liver, pancreas, synovium, skin, and even in the brain Mushahary et al. The discovery of MSCs and their properties has increased the interest in deepening knowledge over their therapeutic features. MSCs are an excellent candidate for cell therapy since they are easily accessible — tissue collection and isolation are relatively simple, and proliferate in vitro.

MSCs are easily preserved, maintaining their potential, and clinical trials have been showing promising results Andrzejewska et al. Firstly studied because of their potential in Regenerative Medicine, other mechanisms of action have been studied and investigated in different areas like immunomodulation and inflammatory process, as well as the paracrine effects of MSC secretome Caseiro et al.

The attention is now focused on the secretome and EVs as candidates to explain the therapeutic effects of MSCs An et al. Mesenchymal stem cells therapeutic potential toward restauration of tissue function is associated with three different, but complementary, mechanisms. The second mechanisms, as described before, is the multi-lineage differentiation capacity, promoting cell engraftment and tissue regeneration Caplan and Dennis, The third mechanism entails the secretion of bioactive factors, modulating both local and systemic physiological processes Biju and Jack, In animal models, there are several registered successful clinical trials with promising results in several different tissues like myocardial, renal, hepatic, neuronal, among others Shammaa et al.

Therefore, the regenerative properties of MSCs are the main feature studied, with a focus on degenerative conditions that are widely exploited. The most recent approaches in regenerative medicine employ scaffolds Pedrosa et al. Apart from their tissue regeneration potential, MSCs have been described as modulators of the immune system, attenuating tissue impairment due to inflammatory processes.

The modulation of the immune system by the MSCs is mediated by the secretion of soluble factors and direct contact with immune cells. Studies have reported MSCs interaction and suppression of immune cells, native and adaptive Alvites et al. The ability to modulate the immune system by cell contact has been investigated, and it is specially of benefit when considering autoimmune conditions and neurodegenerative disorders Shammaa et al.

The secretome includes soluble proteins, free nuclei acids, lipids, EVs among others. It has other advantages like the storage without potentially toxic cryoprotectors, it is more economic and the time of expansion and maintenance can be considerably reduced. EVs, elements of the MSCs secretome, deserve a specific mention due to the recently accelerated studies of its clinical applications. EVs are exosomes, microvesicles and apoptotic bodies, that transport biologically active molecules and genetic information to target cells, thus affecting their potential and function Trohatou and Roubelakis, According to the WHO, the control of COVID has mainly directed on infection prevention, case detection, and monitoring, since the currently approved treatments are of support and not directly envisioning the cure of the pathology.

Although vaccines are being developed in order to reduce the infection rate of COVID, a developing demand to cure the increasing number of patients who develop pneumonia and other critical symptoms is emerging. The other MSCs available for clinical application are the ones from the adipose tissue, umbilical cord tissue and blood, amniotic membrane and dental pulp Atluri et al. According to recent publications and by consulting the site www.

As an important cell population, MSCs have the potential to conduct to very promising outcomes, when considered for the treatment of lung disease. The regulation of the immune system in the lung, by these cells, entails modulation of activation and effector function of immune cells, suppressing of infiltrated cells and diminishing edema Liu et al.

Researchers confirmed that UC-MSCs presented effective results for the restoration of damaged alveolar fluid clearance and protein permeability of influenza A infected alveolar epithelial cells Fujita et al. Clinical studies made in patients with Influenza H7N9 virus, which presented symptoms such as ARDS, lung failure, and fulminant pneumonia, showed that MSCs are a promising choice for treating virus-induced pneumonia. The transplantation of MSCs significantly lowered the mortality rate compared with the control group, with no adverse effects.

The results suggest MSCs improved the survival rate. MSCs can affect the performance of immune cells, both adaptive and innate, and therefore, MSCs therapy can theoretically inhibit the over-triggering of the immune system and promoting endogenous repair following SARS-CoV-2 infection. Several countries have begun clinical studies on MSCs therapies, and some positive results have been published. Initially, the patient showed neutrophil increase and lymphocyte decreased, and was treated with several antiviral drugs, while being subjected to non-invasive mechanical ventilation.

The vital signs improved after the second MSCs administration as other symptoms gradually disappeared. Following, the patient was removed from the ventilator, with a normal number of immune system blood cells. A different group in China of 7 patients with COVID were selected, one with critical diagnosis, 4 with severe diagnosis, and 2 showing moderate symptoms.

Three additional patients with severe diagnoses were chosen as placebo control. All patients presented pyrexia, breath impairment, and thus low oxygenation rates, and pneumonia. Patients were kept on observation during 2 weeks recovery period. Mitigation of the symptoms was observed 2—4 days after treatment, along with a decrease in pneumonia infiltration, with no apparent adverse effects. This study as the one previously described, demonstrated MSCs intravenous infusion as a safe and efficient therapeutic alternative for treating COVID patients Golchin et al.

As mention before, as the immune system is over-triggered it leads to a cytokine storm. The cytokine storm is one of the worst consequences of the disease with the production of inflammatory cytokine accompanied by a weak interferon response. Both studies presented before, included patients with those characteristics.

However, the immunomodulation capacity of MSCs was the key to the promising results obtained and transplantation of MSCs also presented excellent outcomes. Suppressing over-triggering of the immune system and enhancing of the endogenous microenvironment repair capacity are some of the potential of MSCs therapies.

By inhibiting pulmonary vascular endothelial cell apoptosis, enhancing the recovery of VE cadherin, and reducing pro-inflammatory factors, MSCs control inflammation and protect the lung endothelial barrier Wang et al. In both studies intravenous infusion was applied, and it seems to be the most beneficial route of administration due to the fact that, some MSCs concentrate in the lung tissue, after intravenous infusion.

Intuitively, this should likely be beneficial and enhance the pulmonary microenvironment recovery, protecting alveolar epithelial cells, preventing fibrotic tissue formation, thus improving pulmonary function Bulut and Kato, ; Madabhavi et al. The positive results of those two studies are thought to be related to immunomodulatory properties of MSCs as well as MSCs differentiation potential that can avoid lung tissue impairment, by blocking the cytokine storm and by promoting regenerative and reconstructive processes on the affected tissue.

Furthermore, MSCs secretion of paracrine factors, and their interaction with immune cells, leads to immunomodulation and a robust anti-inflammatory activity Chan et al. Given the urgent need to find out an effective treatment, there are active clinical trials concerning COVID at the date of October 1, , involving several different approaches, several mechanisms of action, biomolecules and drugs.

Knowing the potential of MSCs, and based on positive results already obtained, several clinical trials using MSCs have already began or are outlined to start shortly. Of the 62 trials, 16 are located in the American continent, 9 are located in Europe, 11 in East Asia, and the other 26 are distributed over the remaining continents. Notably, 57 of the clinical trials are in Phase 1 or Phase 2, research phases to describe and collect preliminary data on the drug performance in people suffering with the disease, and 3 clinical trials are already in Phase 3, a phase of research that collects information on the pharmaceutical safety and effectiveness, analyzing diverse populations, dosages and application of the drug combined with others research, in the ClinicalTrials.

The current pandemic we are facing, that has not yet shown signs of weakening, is one of the great scourges of recent years and considering the need for mitigation, envisioning at keeping mortality rates low, there is an urgent need to discover effective mechanisms of prevention and therapies. Global efforts are focused on research and development of new therapies, testing different approaches, where MSCs based-therapies standing out.

These are cell-membrane receptors, widely distributed, and particularly in alveolar cells. In addition to the mild symptoms as fever, cough, muscular soreness, expectoration, and dyspnea, COVID can trigger an immune system overreaction, causing a cytokine storm followed by edema, inefficient gas exchange, ARDS, cardiac impairment, and secondary infection that can lead to death. The currently available cure of the COVID disease is mainly dependent on the immune system function of the patient, therefore, avoiding cytokine overproduction may be decisive to recovery of SARS-CoV-2 patients.

The immunomodulatory properties of MSCs can prevent lung tissue impairment by inhibiting pro-inflammatory cytokines overproduction and by promoting regeneration of the damaged tissue, as MSCs secrete a variety of paracrine factors, responsible for their immunomodulation and anti-inflammatory properties.

Stem cell therapy, especially MSCs can potentially be an ideal therapy or be part of a combination of therapies to treat COVID patients, nonetheless, since the number of patients who underwent this kind of treatment is still restricted, more studies with larger samples are needed to validate this therapeutic option, to comprehend the SARS-CoV-2 mechanism of action and to optimize this therapeutic option, by applying randomized studies promoting safety and efficacy of MSCs application on COVID disease.

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Alvites, R. Cell Biol. Peripheral Nerves-Injuries, Disorders and Treatment. London: IntechOpen. Google Scholar. An, T. Stem Cell Rev. Andrzejewska, A. Stem Cells 37, — Atluri, S. Pain Physician 23, E71—E Barry, F.

Berebichez-Fridman, R. Sources and clinical applications of mesenchymal stem cells state-of-the-art review. Sultan Qaboos Univ. Stem Cells Int. Biju, P. Mesenchymal Stem Cells as Therapeutics. Branquinho, M. Kaoud London: Intech. Bulut, C. Epidemiology of covid Caplan, A.

The mesengenic process. Clinics in Plastic Surgery 21, — Lanza, E. Thomas, B. Hogan, R. Pedersen, D Melton, and J. Thomson et al. Amsterdam: Elsevier , — Mesenchymal stem cells: Time to change the name! Stem Cells Transl. Mesenchymal stem cells as trophic mediators. Caseiro, A. PLoS One 14, 1— Procedia Engine. Chan, J. Development and evaluation of novel real-time reverse transcription-PCR assays with locked nucleic acid probes targeting leader sequences of human-pathogenic coronaviruses.

Chen, J. Engineering eng. Choudhery, M. Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation. Crisan, M. Cell Stem Cell 3, — Delorme, B. The human nose harbors a niche of olfactory ectomesenchymal stem cells displaying neurogenic and osteogenic properties. Stem Cells Dev. Denton, A. Stromal cells in the tumor microenvironment. Dominici, M. Minimal criteria for defining multipotent mesenchymal stromal cells.

The International Society for Cellular Therapy position statement. Cytotherapy 8, — Friedenstein, A. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues: Cloning in vitro and retransplantation in vivo. Transplantation 17, — Frieedenstein, A. Hetrotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoetic tissue. Transplantacion Fujita, Y. Ge, L. Secretome of olfactory mucosa mesenchymal stem cell, a multiple potential stem cell.

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Bone 13, 81— Hu, B. Khatri, M. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model. Stem Cell Res. Khoury, M. Kurenkova, A. Cell Dev. Lanza, R. Essentials of Stem Cell Biology. Amsterdam: Elsevier. Li, C. Chimica Acta , 35— Li, N. Interactions between mesenchymal stem cells and the immune system. Life Sci. Li, Q. Early transmission dynamics in Wuhan. China, of novel coronavirus-infected pneumonia.

Liu, S. Madabhavi, I. CoviD A review. Monaldi Arch. Chest Dis. Mushahary, D. Isolation, cultivation, and characterization of human mesenchymal stem cells. Cytometry Part A 93, 19— Pedrosa, S. Scaffolds for peripheral nerve regeneration, the importance of in vitro and in vivo studies for the development of cell-based therapies and biomaterials: state of the art. Scaffolds Tissue Engine. Effective freezing methods for adult and pre-pubertal testicular tissue are available [ ].

Qiuwan et al. For now, reaching successful infertility treatments in humans appears to be only a matter of time, but there are several challenges to overcome. First, the process needs to have high efficiency; second, the chances of forming tumours instead of eggs or sperm must be maximally reduced. The last barrier is how to mature human sperm and eggs in the lab without transplanting them to in vivo conditions, which could cause either a tumour risk or an invasive procedure.

In neuroscience, the discovery of neural stem cells NSCs has nullified the previous idea that adult CNS were not capable of neurogenesis [ , ]. Neural stem cells are capable of improving cognitive function in preclinical rodent models of AD [ , , ]. Awe et al. PD is an ideal disease for iPSC-based cell therapy [ ]. Although the results were not uniform, they showed that therapies with pure stem cells are an important and achievable therapy.

Teeth represent a very challenging material for regenerative medicine. They are difficult to recreate because of their function in aspects such as articulation, mastication, or aesthetics due to their complicated structure. Currently, there is a chance for stem cells to become more widely used than synthetic materials.

Teeth have a large advantage of being the most natural and non-invasive source of stem cells. For now, without the use of stem cells, the most common periodontological treatments are either growth factors, grafts, or surgery. For example, there are stem cells in periodontal ligament [ , ], which are capable of differentiating into osteoblasts or cementoblasts, and their functions were also assessed in neural cells [ ].

Tissue engineering is a successful method for treating periodontal diseases. Stem cells of the root apical areas are able to recreate periodontal ligament. One of the possible methods of tissue engineering in periodontology is gene therapy performed using adenoviruses-containing growth factors [ ]. As a result of animal studies, dentin regeneration is an effective process that results in the formation of dentin bridges [ ].

Enamel is more difficult to regenerate than dentin. After the differentiation of ameloblastoma cells into the enamel, the former is destroyed, and reparation is impossible. Medical studies have succeeded in differentiating bone marrow stem cells into ameloblastoma [ ]. Healthy dental tissue has a high amount of regular stem cells, although this number is reduced when tissue is either traumatized or inflamed [ ]. There are several dental stem cell groups that can be isolated Fig.

Localization of stem cells in dental tissues. Periodontal ligaments stem cells are located in the periodontal ligament. Apical papilla consists of stem cells from the apical papilla SCAP. These were the first dental stem cells isolated from the human dental pulp, which were [ ] located inside dental pulp Table 2. They have osteogenic and chondrogenic potential. Mesenchymal stem cells MSCs of the dental pulp, when isolated, appear highly clonogenic; they can be isolated from adult tissue e. MSCs differentiate into odontoblast-like cells and osteoblasts to form dentin and bone.

Their best source locations are the third molars [ ]. DPSCs are the most useful dental source of tissue engineering due to their easy surgical accessibility, cryopreservation possibility, increased production of dentin tissues compared to non-dental stem cells, and their anti-inflammatory abilities. These cells have the potential to be a source for maxillofacial and orthopaedic reconstructions or reconstructions even beyond the oral cavity.

DPSCs are able to generate all structures of the developed tooth [ ]. In particular, beneficial results in the use of DPSCs may be achieved when combined with other new therapies, such as periodontal tissue photobiomodulation laser stimulation , which is an efficient technique in the stimulation of proliferation and differentiation into distinct cell types [ ]. DPSCs can be induced to form neural cells to help treat neurological deficits.

Stem cells of human exfoliated deciduous teeth SHED have a faster rate of proliferation than DPSCs and differentiate into an even greater number of cells, e. SHED do not undergo the same ethical concerns as embryonic stem cells. DPSCs alone were tested and successfully applied for alveolar bone and mandible reconstruction [ ]. These cells are used in periodontal ligament or cementum tissue regeneration.

PDLSCs exist both on the root and alveolar bone surfaces; however, on the latter, these cells have better differentiation abilities than on the former [ ]. PDLSCs have become the first treatment for periodontal regeneration therapy because of their safety and efficiency [ , ]. These cells are mesenchymal structures located within immature roots. They are isolated from human immature permanent apical papilla. SCAP are the source of odontoblasts and cause apexogenesis. These stem cells can be induced in vitro to form odontoblast-like cells, neuron-like cells, or adipocytes.

These cells are loose connective tissues surrounding the developing tooth germ. DFCs contain cells that can differentiate into cementoblasts, osteoblasts, and periodontal ligament cells [ , ]. Additionally, these cells proliferate after even more than 30 passages [ ]. DFCs are most commonly extracted from the sac of a third molar. When DFCs are combined with a treated dentin matrix, they can form a root-like tissue with a pulp-dentin complex and eventually form tooth roots [ ].

Dental pulp stem cells can differentiate into odontoblasts. There are few methods that enable the regeneration of the pulp. The first is an ex vivo method. Proper stem cells are grown on a scaffold before they are implanted into the root channel [ ].

The second is an in vivo method. This method focuses on injecting stem cells into disinfected root channels after the opening of the in vivo apex. Additionally, the use of a scaffold is necessary to prevent the movement of cells towards other tissues.

For now, only pulp-like structures have been created successfully. Methods of placing stem cells into the root channel constitute are either soft scaffolding [ ] or the application of stem cells in apexogenesis or apexification. Immature teeth are the best source [ ]. Nerve and blood vessel network regeneration are extremely vital to keep pulp tissue healthy. The potential of dental stem cells is mainly regarding the regeneration of damaged dentin and pulp or the repair of any perforations; in the future, it appears to be even possible to generate the whole tooth.

Such an immense success would lead to the gradual replacement of implant treatments. Mandibulary and maxillary defects can be one of the most complicated dental problems for stem cells to address. In , it was reported that it is possible to grow teeth from stem cells obtained extra-orally, e.

Pluripotent stem cells derived from human urine were induced and generated tooth-like structures. The physical properties of the structures were similar to natural ones except for hardness [ ]. Nonetheless, it appears to be a very promising technique because it is non-invasive and relatively low-cost, and somatic cells can be used instead of embryonic cells.

More importantly, stem cells derived from urine did not form any tumours, and the use of autologous cells reduces the chances of rejection [ ]. Over recent years, graphene and its derivatives have been increasingly used as scaffold materials to mediate stem cell growth and differentiation [ ].

Both graphene and graphene oxide GO represent high in-plane stiffness [ ]. Because graphene has carbon and aromatic network, it works either covalently or non-covalently with biomolecules; in addition to its superior mechanical properties, graphene offers versatile chemistry. Graphene exhibits biocompatibility with cells and their proper adhesion.

It also tested positively for enhancing the proliferation or differentiation of stem cells [ ]. After positive experiments, graphene revealed great potential as a scaffold and guide for specific lineages of stem cell differentiation [ ]. Graphene has been successfully used in the transplantation of hMSCs and their guided differentiation to specific cells. The acceleration skills of graphene differentiation and division were also investigated.

It was discovered that graphene can serve as a platform with increased adhesion for both growth factors and differentiation chemicals. Extracellular vesicles EVs can be released by virtually every cell of an organism, including stem cells [ ], and are involved in intercellular communication through the delivery of their mRNAs, lipids, and proteins. As Oh et al. IncRNAs can bind to specific loci and create epigenetic regulators, which leads to the formation of epigenetic modifications in recipient cells.

Because of this feature, exosomes are believed to be implicated in cell-to-cell communication and the progression of diseases such as cancer [ ]. Recently, many studies have also shown the therapeutic use of exosomes derived from stem cells, e. In intrinsic skin ageing, on the other hand, the loss of elasticity is a characteristic feature. The skin dermis consists of fibroblasts, which are responsible for the synthesis of crucial skin elements, such as procollagen or elastic fibres. These elements form either basic framework extracellular matrix constituents of the skin dermis or play a major role in tissue elasticity.

Fibroblast efficiency and abundance decrease with ageing [ ]. Huh et al. It was discovered that, in addition to the induction of fibroblast physiology, hAFSC transplantation also improved diseases in cases of renal pathology, various cancers, or stroke [ , ]. Oh [ ] also presented another option for the treatment of skin wounds, either caused by physical damage or due to diabetic ulcers. Induced pluripotent stem cell-conditioned medium iPSC-CM without any animal-derived components induced dermal fibroblast proliferation and migration.

During the crucial step of proliferation, fibroblasts migrate and increase in number, indicating that it is a critical step in skin repair, and factors such as iPSC-CM that impact it can improve the whole cutaneous wound healing process. Paracrine actions performed by iPSCs are also important for this therapeutic effect [ ]. Bae et al. It was also demonstrated that iPSC factors can enhance skin wound healing in vivo and in vitro when Zhou et al.

Peng et al. However, the research article points out that the procedure was accomplished only on in vitro acquired retina. Although stem cells appear to be an ideal solution for medicine, there are still many obstacles that need to be overcome in the future. One of the first problems is ethical concern. The most common pluripotent stem cells are ESCs. Therapies concerning their use at the beginning were, and still are, the source of ethical conflicts. The reason behind it started when, in , scientists discovered the possibility of removing ESCs from human embryos.

Stem cell therapy appeared to be very effective in treating many, even previously incurable, diseases. The problem was that when scientists isolated ESCs in the lab, the embryo, which had potential for becoming a human, was destroyed Fig. Because of this, scientists, seeing a large potential in this treatment method, focused their efforts on making it possible to isolate stem cells without endangering their source—the embryo.

Use of inner cell mass pluripotent stem cells and their stimulation to differentiate into desired cell types. For now, while hESCs still remain an ethically debatable source of cells, they are potentially powerful tools to be used for therapeutic applications of tissue regeneration.

Because of the complexity of stem cell control systems, there is still much to be learned through observations in vitro. For stem cells to become a popular and widely accessible procedure, tumour risk must be assessed. New cells need to have the ability to fully replace lost or malfunctioning natural cells.

Additionally, there is a concern about the possibility of obtaining stem cells without the risk of morbidity or pain for either the patient or the donor. Uncontrolled proliferation and differentiation of cells after implementation must also be assessed before its use in a wide variety of regenerative procedures on living patients [ ]. One of the arguments that limit the use of iPSCs is their infamous role in tumourigenicity.

There is a risk that the expression of oncogenes may increase when cells are being reprogrammed. In , a technique was discovered that allowed scientists to remove oncogenes after a cell achieved pluripotency, although it is not efficient yet and takes a longer amount of time.

The process of reprogramming may be enhanced by deletion of the tumour suppressor gene p53, but this gene also acts as a key regulator of cancer, which makes it impossible to remove in order to avoid more mutations in the reprogrammed cell. The low efficiency of the process is another problem, which is progressively becoming reduced with each year. The use of transcription factors creates a risk of genomic insertion and further mutation of the target cell genome. For now, the only ethically acceptable operation is an injection of hESCs into mouse embryos in the case of pluripotency evaluation [ ].

Pioneering scientific and medical advances always have to be carefully policed in order to make sure they are both ethical and safe. Because stem cell therapy already has a large impact on many aspects of life, it should not be treated differently. Currently, there are several challenges concerning stem cells. First, the most important one is about fully understanding the mechanism by which stem cells function first in animal models.

This step cannot be avoided. For the widespread, global acceptance of the procedure, fear of the unknown is the greatest challenge to overcome. The efficiency of stem cell-directed differentiation must be improved to make stem cells more reliable and trustworthy for a regular patient. The scale of the procedure is another challenge. Future stem cell therapies may be a significant obstacle. Transplanting new, fully functional organs made by stem cell therapy would require the creation of millions of working and biologically accurate cooperating cells.

Bringing such complicated procedures into general, widespread regenerative medicine will require interdisciplinary and international collaboration. Immunological rejection is a major barrier to successful stem cell transplantation. With certain types of stem cells and procedures, the immune system may recognize transplanted cells as foreign bodies, triggering an immune reaction resulting in transplant or cell rejection.

Further development and versatility of stem cells may cause reduction of treatment costs for people suffering from currently incurable diseases. When facing certain organ failure, instead of undergoing extraordinarily expensive drug treatment, the patient would be able to utilize stem cell therapy.

The effect of a successful operation would be immediate, and the patient would avoid chronic pharmacological treatment and its inevitable side effects. Although these challenges facing stem cell science can be overwhelming, the field is making great advances each day. Stem cell therapy is already available for treating several diseases and conditions.

Their impact on future medicine appears to be significant. After several decades of experiments, stem cell therapy is becoming a magnificent game changer for medicine. With each experiment, the capabilities of stem cells are growing, although there are still many obstacles to overcome. Regardless, the influence of stem cells in regenerative medicine and transplantology is immense.

Currently, untreatable neurodegenerative diseases have the possibility of becoming treatable with stem cell therapy. Tissue banks are becoming increasingly popular, as they gather cells that are the source of regenerative medicine in a struggle against present and future diseases. With stem cell therapy and all its regenerative benefits, we are better able to prolong human life than at any time in history.

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J Arthroplast. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev. Sahin E, Depinho RA. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Using DNA methylation profiling to evaluate biological age and longevity interventions. Cell Metab. Gerontology, Rejuvenation by cell reprogramming: a new horizon in. Rodolfo G. In vivo amelioration of age-associated hallmarks by partial reprogramming.

Transient transcription factor OSKM expression is key towards clinical translation of in vivo cell reprogramming. Bringing the age-related macular degeneration high-risk allele age-related maculopathy susceptibility 2 into focus with stem cell technology. Liu J. Induced pluripotent stem cell-derived neural stem cells: new hope for stroke? Stem Cell ResTher. Kroon E, Martinson LA, et al. Banking stem cells from human exfoliated deciduous teeth.

J Clin Pediatr Dent. Mao JJ. Stem cells and the future of dental care. New York State Dental J. Reznick, Jay B. Continuing education: stem cells: emerging medical and dental therapies for the dental Professional. Dentaltown Magazine. Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues.

Dental pulp tissue engineering with stem cells from exfoliated. J Endod. Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Sadri-Ardekani H, Atala A. Testicular tissue cryopreservation and spermatogonial stem cell transplantation to restore fertility: from bench to bedside. Human amniotic epithelial cells inhibit granulosa cell apoptosis induced by chemotherapy and restore the fertility.

Adult neural stem cells in the mammalian central nervous system. Cell Res. Stem cells for the treatment of neurodegenerative diseases. J Med Invest. Article PubMed Google Scholar. Transplantation of primed or unprimed mouse embryonic stem cell-derived neural precursor cells improves cognitive function in Alzheimerian rats. Byrne JA. Developing neural stem cell-based treatments for neurodegenerative diseases.

Generation and characterization of transgene-free human induced pluripotent stem cells and conversion to putative clinical-grade status. Peng J, Zeng X. The role of induced pluripotent stem cells in regenerative medicine: neurodegenerative diseases. Stem cells and periodontal regeneration.

Aust Dent J. Investigation of multipotent postnatal stem cells from human periodontal ligament. Gene therapeutics for periodontal regenerative medicine. Dent Clin North Am. The efficacy of mesenchymal stem cells to regenerate and repair dental structures.

OrthodCraniofac Res. Dentin regeneration by dental pulp stem cell therapy with recombinant human bone morphogenetic protein. J Dent Res. Bone marrow cells can give rise to ameloblast-like cells. MiR modulates osteogenic differentiation through a coherent feed-forward loop in mesenchymal stem cells isolated from periodontal ligaments of patients with periodontitis. Dental stem cells harvested from third molars combined with bioactive glass can induce signs of bone formation in vitro. J Oral Maxillofac Res.

Published Mar Mesenchymal stem cells in preclinical cancer cytotherapy: a systematic review. Bansal R, Jain A. Current overview on dental stem cells applications in regenerative dentistry. J Nat Sci Biol Med. Mesenchymal stem cells derived from dental pulp: a review. Stem Cells Int. Making use of lasers in periodontal treatment: a new gold standard? Photomed Laser Surg. SHED: stem cells from human exfoliated deciduous teeth. Purified human dental pulp stem cells promote osteogenic regeneration.

Multifaceted neuro-regenerative activities of human dental pulp stem cells for functional recovery after spinal cord injury. Neurosci Res. Eur Cell Mater. Characterization of stem cells from alveolar periodontal ligament. Tissue Eng.

Part A. Validation of human periodontal ligament-derived cells as a reliable source for cytotherapeutic use. J Clin Periodontol. Treatment of periodontal intrabony defects using autologous periodontal ligament stem cells: a randomized clinical trial. Arch Oral Biol. Dental follicle progenitor cell heterogeneity in the developing mouse periodontium. Progenitor cells from dental follicle are able to form cementum matrix in vivo.

Connect Tissue Res. Heterogeneous dental follicle cells and the regeneration of complex periodontal tissues. Tissue Engineering. Bai, Yudi et al. Dental pulp tissue engineering with stem cells from exfoliated deciduous teeth. Effects of alginate, hydrogels and TGF-beta 1 on human dental pulp repair in vitro. Connect Tissue Res 2. Dental stem cells and their potential role in apexogenesis and apexification.

Int Endod J. Cell Regen Lond. July 30, , 2 1 , pp. Craig J. Taylor, Eleanor M. Bolton, and J. Immunological considerations for embryonic and induced pluripotent stem cell banking,. Nayak, H. Andersen, V. Makam, C. Khaw, S. Bae, X. Xu, P. Ee, J. Ahn, B. Hong, G. Pastorin, B. Ozyilmaz, ACS Nano, 5 6 , pp. Graphene for controlled and accelerated osteogenic differentiation of human mesenchymal stem cells,. ACS Nano.

Origin of enhanced stem cell growth and differentiation on graphene and graphene oxide. When stem cells meet graphene: opportunities and challenges in regenerative medicine. Transfer of microRNAs by embryonic stem cell microvesicles. Oh, Myeongsik, et al. Exosomes derived from human induced pluripotent stem cells ameliorate the aging of skin fibroblasts. Ramirez MI. Technical challenges of working with extracellular vesicles. Valadi H, et al.

Cell Biol. Mateescu B, et al. Nawaz M, et al. Extracellular vesicles: evolving factors in stem cell biology. Article ID Helfrich, Y. Overview of skin aging and photoaging. The hallmarks of fibroblast ageing, mechanisms of ageing and development, , , Pages 26— Effect of conditioned media collected from human amniotic fluid-derived stem cells hAFSCs on skin regeneration and photo-aging. Tissue Eng Regen Med. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.

Am J Physiol Renal Physiol.

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A solution to these problems has been and is still being developed, with laboratory-grown organs holding much promise. While the potential of stem cells research is endless it comes with a number of ethical considerations. Stem cells are like blank cells that can transform into whatever cells they are surrounded by; if placed in the liver they can become liver cells, the same in the heart or the a kidney.

However, the research remains controversial because the richest source of stem cells needed to further the research are most often found in the tissue of aborted fetuses. This brings up many ethical questions that have Get your literature review done by professional writers!

Further investigation of compounds would include if they are active, inhibiting, and do they help further characterize the target. She documents tubulin and several others that have potential. Her conclusion confirms that Teachers are seeing this integration of gaming into the classroom with such things as Smartboards and Ipads to utilize the tech skills that students are developing. Unfortunately most teachers relate gaming to negative effects which are major concerns amongst most school faculties.

As a future teacher, I want to know how gaming is affecting the students in a positive, negative, and social aspect. My experiences with gaming have been positive but how I view the amount of Science teaching has the objective of educating scientifically literate citizens while genetic and genomic technologies addresses the science courses. The prime goal of the educational policies in all industrialized societies is to provide science literacy in education.

The Western world applies a similar set of scientific standards. The key role attributes to genes as determinants of health, behavior, and human identity. Molecular Genetics and Genomics say that genetics is a scientific field with the concern of science literacy. The media Unity is no longer the major goal and the construction of a society that is capable of mobilizing its resources to combat backwardness and enhance the financial condition of the state has taken a backseat.

The elite class has instead tried to enforce a brand of unity via Islam and Arab nationalism that has alienated portions of the population not present MicroRNAs are crucial for the development of vertebrates due to the fact that depletion of the components of the miRNA processing pathway, or interfering with maturation of miRNAs, is not compatible with life Wiemer, The miRNA The miRNA genes are dispersed across the genome in gene clusters or as single genes.

Register Internal server error. Please try again later. Forgot password? Password recovery email has been sent to email email. Type of Paper. Essay Topics. Educational Tools. Need more Stem Literature Review examples? Introduction Annotated bibliography Over the years there has been unending debate of whether the state should use federal funding to support the field of stem cell research or whether stem cell research should be allowed at all.

Read more. Stem-Cell Research. Cell Research. Abstract The number of people being affected by various diseases that require them to have organ transplants increases every day. Organ Transplantation. Haruko Obokata. Few randomized controlled trials provide level 3 evidence-based information for or against autologous stem cell transplantation. Such trials are notoriously difficult to perform because of problems in randomly allocating patients between treatment arms of radically different intensity.

More commonly, stem cell transplantation is introduced into patient management because of failure to achieve satisfactory outcomes with standard treatments. Research groups may concentrate on a particular disease to establish the feasibility and outcome of stem cell transplantation. After results are published, some approaches are gradually incorporated into standard clinical practice. Improvements in HLA matching, the treatment of graft-versus-host disease, and supportive therapy have enabled the wider application of allogeneic transplantation to more diseases, including some nonmalignant but severely debilitating conditions such as thalassemia and inherited metabolic disorders.

Autologous stem cell transplantations allow the escalation of cytotoxic treatments and reduce the period of neutropenia after treatment. They were introduced for patients with disorders in which higher doses of conventional chemotherapy might be expected to eradicate the disease—such as neuroblastoma, 20 non-Hodgkin's lymphoma, and Hodgkin's disease in second remission.

Improved survival in patients in this last, difficult group 21 led to studies evaluating the merits of autologous transplantation for Hodgkin's disease in first remission and as a means of escalating treatment in solid tumors such as breast and ovarian cancers. Improvements in harvesting techniques and the growth of stem cells in the laboratory see box will lead to increased safety of autografts and an expanding list of indications. Purging of stem cell transplants may become routine to reduce contamination with tumor cells.

Reducing the intensity of conditioning regimens for allografts will improve safety and increase applicability. Such transplantations may be followed by higher relapse rates, but these will be offset by the use of graft-versus-tumor effects by the infusion of donor lymphocytes. Techniques that offer a possibly higher cure rate than standard approaches will become suitable for many older patients with hematologic conditions and cancer.

Improved immunosuppression protocols may allow transplantation across different HLA types. Ongoing research programs with possible clinical applications include the development of vehicles for gene therapy, tumor-specific vaccines, and radionuclide conditioning agents.

Worldwide, more than phase I and II trials of gene therapy have now been undertaken or completed for cancer and monogenic disorders. Growth of stem cells in the laboratory, enabling wider use of cord blood donations in adults. Expansion of indications for transplantation, such as various solid tumors and severe autoimmune conditions.

Tumor-specific vaccines to boost patients' immune response to their tumor are now entering clinical trials for non-Hodgkin's lymphoma. Radionuclide-labeled conditioning agents that have been bound to antibodies directed against stem cell antigens is an attempt to target conditioning radiotherapy to bone marrow cells so as to allow a higher dose of irradiation to the marrow with fewer systemic side effects. The next 5 to 10 years will be an exciting time for hematology.

Currently, we have patients who might benefit from allogeneic transplant but who do not have a matched donor. The continued expansion of cord blood banks should alleviate this problem, especially if the banks can store donations from ethnic minorities in satisfactory numbers.

The expansion of stem cell numbers from these small donations by their culture in the laboratory will, if successful, increase the number of allogeneic transplantations being performed and possibly increase the number of patients being cured.

In addition, we see closer collaboration with other medical specialists being necessary to assess the place of autologous transplantation in the treatment of more solid tumors and currently intractable autoimmune conditions. Competing interests: None declared. For further reading, we recommend the guide to Internet resources for cancer at www. National Center for Biotechnology Information , U.

Journal List West J Med v. West J Med. Author information Copyright and License information Disclaimer. Correspondence to: Dr Lennard ku. Open in a separate window. Figure 1. Matched unrelated donors To make transplantations available to a greater number of eligible patients, registries of volunteer bone marrow donors have been developed. Stem cells from umbilical cord blood Cord blood from neonates contains substantial numbers of hemopoietic stem cells, which can be harvested at delivery, frozen, and then transplanted to patients who would not otherwise have a donor figure 2.

Figure 2. Autologous transplantations Autologous transplantation patients are their own donors is now the most common form of stem cell transplantation. Reduced-intensity conditioning for allografts Conventional conditioning regimens for patients with leukemia are meant to ablate the patients' marrow and all traces of disease before infusion of donor stem cells.

Donor lymphocyte infusions If a malignant hemopoietic condition relapses after an allogeneic transplantation, lymphocyte infusions from the original donor can return the patient to remission by exploiting the graft-versus-tumor effect. Table 1 Indications for stem cell transplantation. Gene therapy Worldwide, more than phase I and II trials of gene therapy have now been undertaken or completed for cancer and monogenic disorders.

Tumor-specific vaccines Tumor-specific vaccines to boost patients' immune response to their tumor are now entering clinical trials for non-Hodgkin's lymphoma. Radionuclide-labeled conditioning agents Radionuclide-labeled conditioning agents that have been bound to antibodies directed against stem cell antigens is an attempt to target conditioning radiotherapy to bone marrow cells so as to allow a higher dose of irradiation to the marrow with fewer systemic side effects.

References 1. Collection of Philadelphia-negative peripheral blood progenitor cells in unselected patients with chronic granulocytic leukaemia: Northern Regional Haematology Group. Leukemia ; 12 : Hows J, Bradley B. Transplantation for patients without HLA identical siblings. Recent Advances in Haematology.

Vol 8. London: Churchill Livingstone; Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Lancet ; : Gluckman E. Rocha V, Chastang C. Cord blood stem cell transplantation. Baillieres Clin Haematol ; 12 : An economic evaluation of peripheral blood stem cell transplantation as an alternative to autologous bone marrow transplantation in multiple myeloma.

Bone Marrow Transplant ; 18 : Bone Marrow Transplant ; 17 : Perry AR, Mackinnon S. Adoptive immunotherapy post bone-marrow transplantation. Blood Rev ; 10 : Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases.

Blood ; 91 : Kolb HJ. Vox Sang ; 74 suppl 2 : Ganser A, Karthaus M. Clinical use of hematopoietic growth factors. Curr Opin Oncol ; 8 : Hebart H, Einsele H. Diagnosis and treatment of cytomegalovirus infection. Curr Opin Hematol ; 5 : De Marie S.

New developments in the diagnosis and management of invasive fungal infections. Haematologica ; 85 : Negative selection of autologous peripheral blood stem cells. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe in Bone Marrow Transplant ; 21 : Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma.

J Natl Cancer Inst ; 92 : A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma: Intergroupe Francais du Myelome. N Engl J Med ; :

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As a matter of fact, MSCs present immunomodulatory capacity, so, it is observed their ability to prevent and attenuate the cytokine storm, reducing the morbidity and mortality. This literature review aims at discussing MSCs as a strategy for the medical approach of severe or critical COVID patients and further understanding the impact of MSCs origin and in vitro culture conditioning methods, as well as their characterization, on their therapeutic potential and clinical significance toward COVID disease.

It seems that expanded umbilical cord mesenchymal stem cells UC-MSCs may be the most efficient possible treatment available, associated to supportive therapies, for severe clinical cases Atluri et al. Friedenstein was one of the pioneers in the study of stem cells and the identification of multipotential stromal precursor cells. Based on his s and s discoveries, it was shown that mouse bone marrow BM , like other blood-forming organs, contained clonogenic progenitor cells that, once in culture, could originate fibroblasts and other mesodermal cells.

He also understood that these cells were precursors of cartilage and bone-forming cells but did not belong to the hematopoietic cell lineage Frieedenstein et al. From BM, Friedenstein was also able to isolate adherent cells identical to fibroblasts that grew rapidly in vitro and were able to form clonogenic colonies called colony forming unit-fibroblast [CFU-F]. Cells isolated from CFU-F had the additional ability to differentiate into chondrocytes, osteocytes, osteoblasts and adipocytes in vitro Friedenstein et al.

Haynesworth et al. Subsequently, Barry et al. In the next years, massive interest in MSCs studies was established and, even though BM was exploited as the source organ of MSCs in the first place, quickly adult adipose tissue AT was established as a main niche of MSCs, demonstrating an equally interesting multipotency ex vivo Gomez-Salazar et al. The rapid interest that fell on MSCs, associated with their demonstrated clinical relevance and some controversy associated with the characteristics and nomenclature attributed, raised the need to establish an official and more restricted definition for these cells.

More recently, one work has established MSCs as natural precursors for adventitial cells, perivascular fibroblasts and pericytes, pointing to a stromal origin for MSCs Crisan et al. Recent findings demonstrate that MSCs can be isolated from any mesenchymal tissue or niche that manifests regenerative capacity, and that these cells have basic Stem Cell capabilities such as clonogenic potential, self-renewal, and ability to regenerate tissues in vivo and multi-lineage differentiation capacity.

Some MSCs that are cultured in vitro lack specific identifying markers Lanza et al. MSCs represent an important tool in the development of new possible therapies with applications in regenerative medicine, immunotherapy, tissue engineering, and cell and molecular biology with almost 10, papers published in the last 40 years [search, in the PUBMED. Stem cells can be categorized considering their profile of differentiation and source within the human body.

Discovered originally in the BM, this type of cells is still recognized as the more promising for clinical application and research, although some alternative sources including AT, birth-derived tissues, amniotic fluid AF and placenta, dental pulp DP , olfactory tissues, synovium and synovial fluid, endometrium, muscle, and peripheral blood — have since been identified, as we can see in Figure 2 Berebichez-Fridman and Montero-Olvera, Figure 2.

In theory, MSCs can be isolated from almost any tissue in the human body. Despite this, it is necessary to consider some practical limitations, such as the associated difficulty, the degree of invasion of the collection method and the characteristics of the donor himself. Parameters such as tissue source, isolation technique and the culture medium used can alter the properties of the collected human MSCs.

MSCs can differentiate in the neuroectodermic and endoderm lines, in addition to the already known capacity for mesodermal lineage differentiation Mushahary et al. The developmental origin of mesenchymal tissues, including not only mesoderm but also the cranial neural crest, may be the explanation for this ability. It is important to note that recently it was demonstrated that MSCs are mostly derived from the neural crest and neuroepithelium, even though traditionally it was considered the mesodermal origin Uccelli et al.

Embryonic Stem Cells ESCs are totipotent because they can form both embryonic and extraembryonic structures. Moreover, ESCs can proliferate indefinitely under specific culture conditions and retain the capacity to differentiate into cell types from the three embryonic germ layers. On the other hand, adult stem cells are undifferentiated multipotent stem cells obtained from adult individuals and differentiate into the cell types that constitute their respective source tissue Uccelli et al.

The procedure to obtain BM-MSCs is a highly invasive and can result in pain or infection, making the selection of other sources, like peripheral blood or surgical remnants such as AT, preferable Berebichez-Fridman et al. The cell yield, longevity, and potential for differentiation decrease with donor age Choudhery et al.

About 0. Besides that, these cells continue to be widely used, as they can be effortlessly isolated from a small quantities of aspirate and have a short culture time, being able to double 40 times its numbers in about 8—10 weeks of culture Salem and Thiemermann, In terms of differentiation, BM-MSCs have an advantage when compared to other sources, with high multi-lineage differentiation and proliferation capacity.

This type of stem cell is the most widely investigated, with active studies in arterial hypertension, ischemic heart failure, digestive system, treatment of spinal cord injuries, among others, and therefore is considered to be the gold standard Choudhery et al. Besides their stability in long-term cell cultures, AT-MSCs can expand effectively in vitro and possess high multi-lineage differentiation potential. Its main advantage as a MSCs source is convenience, as human AT is usually abundant throughout the body and is easily accessible through liposuction procedures.

Currently, umbilical cord blood UCB is accepted as a source of hematopoietic stem cells, but also of MSCs and the abundance of UCB, availability of donors, facility of acquisition, and reliability of sample collection are relevant advantages Berebichez-Fridman and Montero-Olvera, UCB-MSCs are more immature than other types of adult stem cells, and do not evoke a strong immune rejection response in an allogeneic recipient.

UCB-MSCs can be cryopreserved in vast quantities for later cultivation and research, but also for the treatment of hematologic pathologies, and possess osteogenic, chondrogenic, adipogenic, and myogenic differentiation potential. Cultured cells obtained from this source can differentiate into mesenchymal lineages, with a high self-renewal capacity and a doubling time of 36 h, maintaining a normal karyotype even at late passages. Placenta-derived MSCs also express embryonic stem cell markers and can differentiate into mesenchymal as well as hepatic, pancreatic, and neuronal lineages Spitzhorn et al.

Peripheral blood stem cells may be mobilized from healthy donors using granulocyte-macrophage colony-stimulating factor GM-CSF. The underlying mechanism involves several adhesion molecules that facilitate the binding of stem cells to BM and their disruption allows for their release into the circulation.

In humans, cartilage and synovium originate from a common pool of cells during synovial joint development. Synovia-derived MSCs are far superior to cells derived from the skeletal muscle and AT, as determined by their in vitro expandability, differentiation potential, and epitope profiles Berebichez-Fridman and Montero-Olvera, Their superior chondrogenic and proliferation potential has been reported by several groups, making these cells fair candidates for cell therapy applications, particularly regarding osteoarticular disorders Branquinho et al.

DP-derived MSCs specialize in odontoblasts, which produce dentin. These cells are obtained from pulp tissue and the periodontal ligament, and are extracted by an enzymatic digestive process or explant method. Different works involving OM-MSCs revealed its fibroblastic-like cytomorphology, development of low density colonies, the plastic-adhesion, the expression of expected surface markers and also the capacity for differentiation, not only the classic tri-differentiation but also other pathways such as neuroglial and myogenic Alvites et al.

Its secretome has also started to be analyzed, and it was possible to identify several bioactive molecules with pro-regenerative and immunomodulatory functions Ge et al. The clinical use of these cells can be advantageous due to their anatomical location, easily accessible, and also to their wide distribution in the nasal cavity. Additionally, previous studies have already shown that OM-MSCs can be maintained in culture for extended periods without chromosomal or tumorigenic changes being observed.

Mesenchymal stem cells are plastic-adherent cell populations, isolated through procedures involving tissue mincing, enzymatic digestion, and cell growth on a plastic surface. The two main procedures are the enzymatic and explant protocols Mushahary et al. In the explant method, one of the earliest techniques applied, the tissue is rinsed with a saline solution and mechanically split into smaller fragments.

Fragments are further placed on a culture dish and covered in adequate culture medium. The enzymatic method entails a more complex protocol. After rinsing with a saline solution and mechanical splitting into smaller fragments, identically to the first steps on the explant method, the tissue is incubated with an enzymatic solution.

As a result, singe cells or aggregates are released and remain suspended in the enzymatic solution. After centrifugation for elimination of the enzymatic solution, the cell pellet is re-suspended in adequate culture medium and seeded in culture dishes. MSCs therapeutic potential toward a specific tissue regeneration lies not only on the MSCs tissue of origin, but also on their potential itself and on their secretion potential of bio-factors with pharmacological properties, the so called secretome.

MSCs protocols between groups regarding isolation, culture conditions and characterization varies immensely, impairing the reproductivity of results between different research groups. A critical parameter when considering MSCs is the cell potential toward regeneration. An improved therapeutic efficacy of MSCs is greatly influenced by optimized culture condition protocols Alvites et al.

Lastly, MSCs most be able to differentiate into three different lineages: osteoblasts, adipocytes and chondroblasts. The homogeneity of these characteristics is relative as different MSCs population express different surface markers, an understandable feature, as MSCs present plasticity, a dynamic capacity to adapt and vary over time to different conditions.

Different antigen sets are applied from different research groups, to characterize these cells, with different outcomes, thus, no specific marker was identified as to uniquely characterize MSCs. MSCs can differentiate into different cell types when an array of differentiation factors is used to mimic osteogenic, chondrogenic, or adipogenic in vitro microenvironment, for instance.

Standardized procedures for culture conditions and MSCs characterization still remains a major challenge. Although the official criteria speak of tri-differentiation, it has long been known that MSCs can follow multiple types of differentiation and that is also a factor in the discussion of these criteria, with some studies suggesting the addition of other criteria factors for MSCs characterization. Some research groups suggest that to profile MSCs we must observe key parameters like CFU-F efficiency, MSC isolation, multilineage differentiation, immunomodulation, telomere length, trophic factor quantification, cumulative growth, and surface phenotype Samsonraj et al.

However, the ISCT guidelines are still the recommended criteria for the isolation and characterization of MSCs and are precise enough to combine the majority of the to-day existing knowledge, recognizing that future research, along with scientific breakthroughs, will probably lead to optimization of the criteria Greif et al. Considering MSCs are an interesting source for autologous transplantation and analysis of their cellular and molecular pathway has been performed, as well as the niche changes, as to assess on the cytokines, chemokines and other bioactive factors role in the differentiation potential of these cells Alvites et al.

MSCs present a great differentiation potential toward mesenchymal lineages. Under specific in vitro inducing conditions, they can differentiate into adipogenic, osteogenic, or chondrogenic lineage. Differentiation can be induced in vitro , when seeding MSCs in specific differentiation supplemented media, as shown in Figure 3. Figure 3. Differentiation potential and the mesengenic process modified from Servier Medical Art, licensed under a Creative Common Attribution 3.

Regarding differentiation into the adipogenic lineage, supplementation includes dexamethasone, indomethacin, insulin, and isobutylmethylxanthine. The differentiation into these three lineages is evaluated as for the presence of fat droplets adipogenesis , proteoglycans and type II collagen synthesis chondrogenesis , or mineralization of calcium deposits and increase in alkaline phosphatase expression osteogenesis Sami et al.

MSCs can differentiate into other lineages, such as the neurogenic, myogenic, tenogenic, and others as it was previously reported by several research groups Branquinho et al. For instance, a process defined as mesengenesis has been reported by Caplan , where MSCs originated myoblasts, ligaments, tendons and other cell types Sami et al. Ever since, MSCs have been reported to originate cells from the heart, peripheral blood, cord blood, muscle, AT, lung, trabecular bone, intestine, kidney, liver, pancreas, synovium, skin, and even in the brain Mushahary et al.

The discovery of MSCs and their properties has increased the interest in deepening knowledge over their therapeutic features. MSCs are an excellent candidate for cell therapy since they are easily accessible — tissue collection and isolation are relatively simple, and proliferate in vitro. MSCs are easily preserved, maintaining their potential, and clinical trials have been showing promising results Andrzejewska et al.

Firstly studied because of their potential in Regenerative Medicine, other mechanisms of action have been studied and investigated in different areas like immunomodulation and inflammatory process, as well as the paracrine effects of MSC secretome Caseiro et al. The attention is now focused on the secretome and EVs as candidates to explain the therapeutic effects of MSCs An et al.

Mesenchymal stem cells therapeutic potential toward restauration of tissue function is associated with three different, but complementary, mechanisms. The second mechanisms, as described before, is the multi-lineage differentiation capacity, promoting cell engraftment and tissue regeneration Caplan and Dennis, The third mechanism entails the secretion of bioactive factors, modulating both local and systemic physiological processes Biju and Jack, In animal models, there are several registered successful clinical trials with promising results in several different tissues like myocardial, renal, hepatic, neuronal, among others Shammaa et al.

Therefore, the regenerative properties of MSCs are the main feature studied, with a focus on degenerative conditions that are widely exploited. The most recent approaches in regenerative medicine employ scaffolds Pedrosa et al. Apart from their tissue regeneration potential, MSCs have been described as modulators of the immune system, attenuating tissue impairment due to inflammatory processes.

The modulation of the immune system by the MSCs is mediated by the secretion of soluble factors and direct contact with immune cells. Studies have reported MSCs interaction and suppression of immune cells, native and adaptive Alvites et al. The ability to modulate the immune system by cell contact has been investigated, and it is specially of benefit when considering autoimmune conditions and neurodegenerative disorders Shammaa et al.

The secretome includes soluble proteins, free nuclei acids, lipids, EVs among others. It has other advantages like the storage without potentially toxic cryoprotectors, it is more economic and the time of expansion and maintenance can be considerably reduced.

EVs, elements of the MSCs secretome, deserve a specific mention due to the recently accelerated studies of its clinical applications. EVs are exosomes, microvesicles and apoptotic bodies, that transport biologically active molecules and genetic information to target cells, thus affecting their potential and function Trohatou and Roubelakis, According to the WHO, the control of COVID has mainly directed on infection prevention, case detection, and monitoring, since the currently approved treatments are of support and not directly envisioning the cure of the pathology.

Although vaccines are being developed in order to reduce the infection rate of COVID, a developing demand to cure the increasing number of patients who develop pneumonia and other critical symptoms is emerging. The other MSCs available for clinical application are the ones from the adipose tissue, umbilical cord tissue and blood, amniotic membrane and dental pulp Atluri et al.

According to recent publications and by consulting the site www. As an important cell population, MSCs have the potential to conduct to very promising outcomes, when considered for the treatment of lung disease. The regulation of the immune system in the lung, by these cells, entails modulation of activation and effector function of immune cells, suppressing of infiltrated cells and diminishing edema Liu et al.

Researchers confirmed that UC-MSCs presented effective results for the restoration of damaged alveolar fluid clearance and protein permeability of influenza A infected alveolar epithelial cells Fujita et al. Clinical studies made in patients with Influenza H7N9 virus, which presented symptoms such as ARDS, lung failure, and fulminant pneumonia, showed that MSCs are a promising choice for treating virus-induced pneumonia.

The transplantation of MSCs significantly lowered the mortality rate compared with the control group, with no adverse effects. The results suggest MSCs improved the survival rate. MSCs can affect the performance of immune cells, both adaptive and innate, and therefore, MSCs therapy can theoretically inhibit the over-triggering of the immune system and promoting endogenous repair following SARS-CoV-2 infection.

Several countries have begun clinical studies on MSCs therapies, and some positive results have been published. Initially, the patient showed neutrophil increase and lymphocyte decreased, and was treated with several antiviral drugs, while being subjected to non-invasive mechanical ventilation.

The vital signs improved after the second MSCs administration as other symptoms gradually disappeared. Following, the patient was removed from the ventilator, with a normal number of immune system blood cells. A different group in China of 7 patients with COVID were selected, one with critical diagnosis, 4 with severe diagnosis, and 2 showing moderate symptoms. Three additional patients with severe diagnoses were chosen as placebo control.

All patients presented pyrexia, breath impairment, and thus low oxygenation rates, and pneumonia. Patients were kept on observation during 2 weeks recovery period. Mitigation of the symptoms was observed 2—4 days after treatment, along with a decrease in pneumonia infiltration, with no apparent adverse effects.

This study as the one previously described, demonstrated MSCs intravenous infusion as a safe and efficient therapeutic alternative for treating COVID patients Golchin et al. As mention before, as the immune system is over-triggered it leads to a cytokine storm. The cytokine storm is one of the worst consequences of the disease with the production of inflammatory cytokine accompanied by a weak interferon response.

Both studies presented before, included patients with those characteristics. However, the immunomodulation capacity of MSCs was the key to the promising results obtained and transplantation of MSCs also presented excellent outcomes.

Suppressing over-triggering of the immune system and enhancing of the endogenous microenvironment repair capacity are some of the potential of MSCs therapies. By inhibiting pulmonary vascular endothelial cell apoptosis, enhancing the recovery of VE cadherin, and reducing pro-inflammatory factors, MSCs control inflammation and protect the lung endothelial barrier Wang et al.

In both studies intravenous infusion was applied, and it seems to be the most beneficial route of administration due to the fact that, some MSCs concentrate in the lung tissue, after intravenous infusion. Intuitively, this should likely be beneficial and enhance the pulmonary microenvironment recovery, protecting alveolar epithelial cells, preventing fibrotic tissue formation, thus improving pulmonary function Bulut and Kato, ; Madabhavi et al. The positive results of those two studies are thought to be related to immunomodulatory properties of MSCs as well as MSCs differentiation potential that can avoid lung tissue impairment, by blocking the cytokine storm and by promoting regenerative and reconstructive processes on the affected tissue.

Furthermore, MSCs secretion of paracrine factors, and their interaction with immune cells, leads to immunomodulation and a robust anti-inflammatory activity Chan et al. Given the urgent need to find out an effective treatment, there are active clinical trials concerning COVID at the date of October 1, , involving several different approaches, several mechanisms of action, biomolecules and drugs.

Knowing the potential of MSCs, and based on positive results already obtained, several clinical trials using MSCs have already began or are outlined to start shortly. Of the 62 trials, 16 are located in the American continent, 9 are located in Europe, 11 in East Asia, and the other 26 are distributed over the remaining continents.

Notably, 57 of the clinical trials are in Phase 1 or Phase 2, research phases to describe and collect preliminary data on the drug performance in people suffering with the disease, and 3 clinical trials are already in Phase 3, a phase of research that collects information on the pharmaceutical safety and effectiveness, analyzing diverse populations, dosages and application of the drug combined with others research, in the ClinicalTrials.

The current pandemic we are facing, that has not yet shown signs of weakening, is one of the great scourges of recent years and considering the need for mitigation, envisioning at keeping mortality rates low, there is an urgent need to discover effective mechanisms of prevention and therapies. Global efforts are focused on research and development of new therapies, testing different approaches, where MSCs based-therapies standing out.

These are cell-membrane receptors, widely distributed, and particularly in alveolar cells. In addition to the mild symptoms as fever, cough, muscular soreness, expectoration, and dyspnea, COVID can trigger an immune system overreaction, causing a cytokine storm followed by edema, inefficient gas exchange, ARDS, cardiac impairment, and secondary infection that can lead to death.

The currently available cure of the COVID disease is mainly dependent on the immune system function of the patient, therefore, avoiding cytokine overproduction may be decisive to recovery of SARS-CoV-2 patients. The immunomodulatory properties of MSCs can prevent lung tissue impairment by inhibiting pro-inflammatory cytokines overproduction and by promoting regeneration of the damaged tissue, as MSCs secrete a variety of paracrine factors, responsible for their immunomodulation and anti-inflammatory properties.

Stem cell therapy, especially MSCs can potentially be an ideal therapy or be part of a combination of therapies to treat COVID patients, nonetheless, since the number of patients who underwent this kind of treatment is still restricted, more studies with larger samples are needed to validate this therapeutic option, to comprehend the SARS-CoV-2 mechanism of action and to optimize this therapeutic option, by applying randomized studies promoting safety and efficacy of MSCs application on COVID disease.

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Alvites, R. Cell Biol. Peripheral Nerves-Injuries, Disorders and Treatment. London: IntechOpen. Google Scholar. An, T. Stem Cell Rev. Andrzejewska, A.

Stem Cells 37, — Atluri, S. Pain Physician 23, E71—E Barry, F. Berebichez-Fridman, R. Sources and clinical applications of mesenchymal stem cells state-of-the-art review. Sultan Qaboos Univ. Stem Cells Int. Biju, P. Mesenchymal Stem Cells as Therapeutics.

Branquinho, M. Kaoud London: Intech. Bulut, C. Epidemiology of covid Caplan, A. The mesengenic process. Although karyology is a crucial procedure in stem cell quality control, the single nucleotide polymorphism SNP array, discussed later, has approximately 50 times higher resolution. Viral testing—When assessing the quality of stem cells, all tests for harmful human adventitious agents must be performed e. This procedure must be performed in the case of non-xeno-free culture agents.

Bacteriology—Bacterial or fungal sterility tests can be divided into culture- or broth-based tests. All the procedures must be recommended by pharmacopoeia for the jurisdiction in which the work is performed. Single nucleotide polymorphism arrays—This procedure is a type of DNA microarray that detects population polymorphisms by enabling the detection of subchromosomal changes and the copy-neutral loss of heterozygosity, as well as an indication of cellular transformation.

The SNP assay consists of three components. The first is labelling fragmented nucleic acid sequences with fluorescent dyes. The second is an array that contains immobilized allele-specific oligonucleotide ASO probes. The last component detects, records, and eventually interprets the signal. Flow cytometry—This is a technique that utilizes light to count and profile cells in a heterogeneous fluid mixture.

It allows researchers to accurately and rapidly collect data from heterogeneous fluid mixtures with live cells. Cells are passed through a narrow channel one by one. During light illumination, sensors detect light emitted or refracted from the cells. The last step is data analysis, compilation and integration into a comprehensive picture of the sample. Phenotypic pluripotency assays—Recognizing undifferentiated cells is crucial in successful stem cell therapy.

Among other characteristics, stem cells appear to have a distinct morphology with a high nucleus to cytoplasm ratio and a prominent nucleolus. Cells appear to be flat with defined borders, in contrast to differentiating colonies, which appear as loosely located cells with rough borders [ 5 ]. It is important that images of ideal and poor quality colonies for each cell line are kept in laboratories, so whenever there is doubt about the quality of culture, it can always be checked according to the representative image.

Embryoid body formation or directed differentiation of monolayer cultures to produce cell types representative of all three embryonic germ layers must be performed. It is important to note that colonies cultured under different conditions may have different morphologies [ 6 ]. Histone modification and DNA methylation—Quality control can be achieved by using epigenetic analysis tools such as histone modification or DNA methylation. When stem cells differentiate, the methylation process silences pluripotency genes, which reduces differentiation potential, although other genes may undergo demethylation to become expressed [ 7 ].

It is important to emphasize that stem cell identity, together with its morphological characteristics, is also related to its epigenetic profile [ 8 , 9 ]. According to Brindley [ 10 ], there is a relationship between epigenetic changes, pluripotency, and cell expansion conditions, which emphasizes that unmethylated regions appear to be serum-dependent. Spontaneous differentiation of hESCs causes the formation of a heterogeneous cell population. There is a different result, however, when commitment signals in forms of soluble factors and culture conditions are applied and enable the selection of progenitor cells.

EBs can be studied instead of embryos or animals to predict their effects on early human development. There are many different methods for acquiring EBs, such as bioreactor culture [ 13 ], hanging drop culture [ 12 ], or microwell technology [ 14 , 15 ]. These methods allow specific precursors to form in vitro [ 16 ]. The essential part of these culturing procedures is a separation of inner cell mass to culture future hESCs Fig.

Rosowski et al. When the colony reaches the appropriate size, cells must be separated. Because the classical utilization of hESCs caused ethical concerns about gastrulas used during procedures, Chung et al. Additionally, Zhang et al. Culturing of pluripotent stem cells in vitro. Three days after fertilization, totipotent cells are formed. Blastocysts with ICM are formed on the sixth day after fertilization. Pluripotent stem cells from ICM can then be successfully transmitted on a dish.

Cell passaging is used to form smaller clusters of cells on a new culture surface [ 21 ]. There are four important passaging procedures. Enzymatic dissociation is a cutting action of enzymes on proteins and adhesion domains that bind the colony. It is a gentler method than the manual passage. It is crucial to not leave hESCs alone after passaging. Solitary cells are more sensitive and can easily undergo cell death; collagenase type IV is an example [ 22 , 23 ].

Manual passage , on the other hand, focuses on using cell scratchers. The selection of certain cells is not necessary. This should be done in the early stages of cell line derivation [ 24 ]. Trypsin utilization allows a healthy, automated hESC passage. Good Manufacturing Practice GMP -grade recombinant trypsin is widely available in this procedure [ 24 ]. However, there is a risk of decreasing the pluripotency and viability of stem cells [ 25 ].

Trypsin utilization can be halted with an inhibitor of the protein rho-associated protein kinase ROCK [ 26 ]. Ethylenediaminetetraacetic acid EDTA indirectly suppresses cell-to-cell connections by chelating divalent cations. Their suppression promotes cell dissociation [ 27 ]. Stem cells require a mixture of growth factors and nutrients to differentiate and develop. The medium should be changed each day. Traditional culture methods used for hESCs are mouse embryonic fibroblasts MEFs as a feeder layer and bovine serum [ 28 ] as a medium.

Martin et al. Feeder layers prevent uncontrolled proliferation with factors such as leukaemia inhibitory factor LIF [ 30 ]. First feeder layer-free culture can be supplemented with serum replacement, combined with laminin [ 31 ]. This causes stable karyotypes of stem cells and pluripotency lasting for over a year. Initial culturing media can be serum e. It is not yet fully known whether culture systems developed for hESCs can be allowed without adaptation in iPSC cultures.

The turning point in stem cell therapy appeared in , when scientists Shinya Yamanaka, together with Kazutoshi Takahashi, discovered that it is possible to reprogram multipotent adult stem cells to the pluripotent state. This new form of stem cells was named iPSCs. One year later, the experiment also succeeded with human cells [ 36 ]. After this success, the method opened a new field in stem cell research with a generation of iPSC lines that can be customized and biocompatible with the patient.

Recently, studies have focused on reducing carcinogenesis and improving the conduction system. Retroviral-mediated transduction induces pluripotency in isolated patient somatic cells. Target cells lose their role as somatic cells and, once again, become pluripotent and can differentiate into any cell type of human body.

This caused a complete reversion of somatic cell development [ 37 ]. The results of his experiment became an immense discovery since it was previously believed that cell differentiation is a one-way street only, but his experiment suggested the opposite and demonstrated that it is even possible for a somatic cell to again acquire pluripotency [ 38 ].

The latter was a discovery made by Davis R. Three genes were found that originally appeared in myoblasts. The enforced expression of only one of the genes, named myogenic differentiation 1 Myod1 , caused the conversion of fibroblasts into myoblasts, showing that reprogramming cells is possible, and it can even be used to transform cells from one lineage to another [ 39 ].

Although pluripotency can occur naturally only in embryonic stem cells, it is possible to induce terminally differentiated cells to become pluripotent again. The process of direct reprogramming converts differentiated somatic cells into iPSC lines that can form all cell types of an organism.

Reprogramming focuses on the expression of oncogenes such as Myc and Klf4 Kruppel-like factor 4. This process is enhanced by a downregulation of genes promoting genome stability, such as p Additionally, cell reprogramming involves histone alteration.

All these processes can cause potential mutagenic risk and later lead to an increased number of mutations. Quinlan et al. Based on those studies, it was confirmed that although there were single mutations in the non-genetic region, there were non-retrotransposon insertions. This led to the conclusion that current reprogramming methods can produce fully pluripotent iPSCs without severe genomic alterations. During the course of development from pluripotent hESCs to differentiated somatic cells, crucial changes appear in the epigenetic structure of these cells.

There is a restriction or permission of the transcription of genes relevant to each cell type. When somatic cells are being reprogrammed using transcription factors, all the epigenetic architecture has to be reconditioned to achieve iPSCs with pluripotency [ 41 ]. However, cells of each tissue undergo specific somatic genomic methylation. This influences transcription, which can further cause alterations in induced pluripotency [ 42 ].

Because pluripotent cells can propagate indefinitely and differentiate into any kind of cell, they can be an unlimited source, either for replacing lost or diseased tissues. At first, fibroblasts were used as a source of iPSCs. Because a biopsy was needed to achieve these types of cells, the technique underwent further research. Researchers investigated whether more accessible cells could be used in the method.

Further, other cells were used in the process: peripheral blood cells, keratinocytes, and renal epithelial cells found in urine. In , pancreatic exocrine cells were shown to be reprogrammed to functional, insulin-producing beta cells [ 43 ]. The best stem cell source appears to be the fibroblasts, which is more tempting in the case of logistics since its stimulation can be fast and better controlled [ 44 ]. The self-renewal and differentiation capabilities of iPSCs have gained significant interest and attention in regenerative medicine sciences.

To study their abilities, a quality-control assay is needed, of which one of the most important is the teratoma formation assay. Teratomas are benign tumours. Teratomas are capable of rapid growth in vivo and are characteristic because of their ability to develop into tissues of all three germ layers simultaneously. This difference may be connected to different differentiation methods and cell origins.

Most commonly, the teratoma assay involves an injection of examined iPSCs subcutaneously or under the testis or kidney capsule in mice, which are immune-deficient [ 47 ]. After injection, an immature but recognizable tissue can be observed, such as the kidney tubules, bone, cartilage, or neuroepithelium [ 30 ].

The injection site may have an impact on the efficiency of teratoma formation [ 48 ]. There are three groups of markers used in this assay to differentiate the cells of germ layers. For the mesoderm, derivatives can be used, e. As ectodermal markers, class III B botulin or keratin can be used for keratinocytes. Teratoma formation assays are considered the gold standard for demonstrating the pluripotency of human iPSCs, demonstrating their possibilities under physiological conditions.

Due to their actual tissue formation, they could be used for the characterization of many cell lineages [ 50 ]. To be useful in therapy, stem cells must be converted into desired cell types as necessary or else the whole regenerative medicine process will be pointless. Understanding and using signalling pathways for differentiation is an important method in successful regenerative medicine.

In directed differentiation, it is likely to mimic signals that are received by cells when they undergo successive stages of development [ 51 ]. The extracellular microenvironment plays a significant role in controlling cell behaviour. By manipulating the culture conditions, it is possible to restrict specific differentiation pathways and generate cultures that are enriched in certain precursors in vitro.

However, achieving a similar effect in vivo is challenging. It is crucial to develop culture conditions that will allow the promotion of homogenous and enhanced differentiation of ESCs into functional and desired tissues. Regarding the self-renewal of embryonic stem cells, Hwang et al. This is because cell and tissue therapy requires the maintenance of large quantities of undifferentiated hESCs, which does not make feeder cells suitable for such tasks. Most directed differentiation protocols are formed to mimic the development of an inner cell mass during gastrulation.

During this process, pluripotent stem cells differentiate into ectodermal, mesodermal, or endodermal progenitors. Mall molecules or growth factors induce the conversion of stem cells into appropriate progenitor cells, which will later give rise to the desired cell type. Each candidate factor must be tested on various concentrations and additionally applied to various durations because the precise concentrations and times during which developing cells in embryos are influenced during differentiation are unknown.

Regarding endoderm formation, a higher activin A concentration may be required [ 58 , 59 ]. There are numerous protocols about the methods of forming progenitors of cells of each of germ layers, such as cardiomyocytes [ 60 ], hepatocytes [ 61 ], renal cells [ 62 ], lung cells [ 63 , 64 ], motor neurons [ 65 ], intestinal cells [ 66 ], or chondrocytes [ 67 ].

In addition, it could also provide the possibility to form exogenous hepatocytes for drug toxicity testing [ 68 ]. Levels of concentration and duration of action with a specific signalling molecule can cause a variety of factors.

Unfortunately, for now, a high cost of recombinant factors is likely to limit their use on a larger scale in medicine. The more promising technique focuses on the use of small molecules. These can be used for either activating or deactivating specific signalling pathways. They enhance reprogramming efficiency by creating cells that are compatible with the desired type of tissue. It is a cheaper and non-immunogenic method. One of the successful examples of small-molecule cell therapies is antagonists and agonists of the Hedgehog pathway.

They show to be very useful in motor neuron regeneration [ 69 ]. Endogenous small molecules with their function in embryonic development can also be used in in vitro methods to induce the differentiation of cells; for example, retinoic acid, which is responsible for patterning the nervous system in vivo [ 70 ], surprisingly induced retinal cell formation when the laboratory procedure involved hESCs [ 71 ]. The efficacy of differentiation factors depends on functional maturity, efficiency, and, finally, introducing produced cells to their in vivo equivalent.

Topography, shear stress, and substrate rigidity are factors influencing the phenotype of future cells [ 72 ]. The control of biophysical and biochemical signals, the biophysical environment, and a proper guide of hESC differentiation are important factors in appropriately cultured stem cells. In the past, protocols used for stem cell transplantation required animal-derived products [ 73 ].

The risk of introducing animal antigens or pathogens caused a restriction in their use. Due to such limitations, the technique required an obvious update [ 74 ]. Now, it is essential to use xeno-free equivalents when establishing cell lines that are derived from fresh embryos and cultured from human feeder cell lines [ 75 ].

In this method, it is crucial to replace any non-human materials with xeno-free equivalents [ 76 ]. There are many organizations and international initiatives, such as the National Stem Cell Bank, that provide stem cell lines for treatment or medical research [ 77 ]. Stem cells have great potential to become one of the most important aspects of medicine. In addition to the fact that they play a large role in developing restorative medicine, their study reveals much information about the complex events that happen during human development.

In the former cell, DNA is arranged loosely with working genes. When signals enter the cell and the differentiation process begins, genes that are no longer needed are shut down, but genes required for the specialized function will remain active. This process can be reversed, and it is known that such pluripotency can be achieved by interaction in gene sequences. Takahashi and Yamanaka [ 78 ] and Loh et al. Many serious medical conditions, such as birth defects or cancer, are caused by improper differentiation or cell division.

Currently, several stem cell therapies are possible, among which are treatments for spinal cord injury, heart failure [ 80 ], retinal and macular degeneration [ 81 ], tendon ruptures, and diabetes type 1 [ 82 ]. Stem cell research can further help in better understanding stem cell physiology. This may result in finding new ways of treating currently incurable diseases. These stem cells appear to provide an accurate paradigm model system to study tissue-specific stem cells, and they have potential in regenerative medicine.

Multipotent haematopoietic stem cell HSC transplantation is currently the most popular stem cell therapy. Target cells are usually derived from the bone marrow, peripheral blood, or umbilical cord blood [ 83 ]. HSCs are responsible for the generation of all functional haematopoietic lineages in blood, including erythrocytes, leukocytes, and platelets.

HSC transplantation solves problems that are caused by inappropriate functioning of the haematopoietic system, which includes diseases such as leukaemia and anaemia. However, when conventional sources of HSC are taken into consideration, there are some important limitations. First, there is a limited number of transplantable cells, and an efficient way of gathering them has not yet been found. There is also a problem with finding a fitting antigen-matched donor for transplantation, and viral contamination or any immunoreactions also cause a reduction in efficiency in conventional HSC transplantations.

Haematopoietic transplantation should be reserved for patients with life-threatening diseases because it has a multifactorial character and can be a dangerous procedure. Stem cells can be used in new drug tests. Each experiment on living tissue can be performed safely on specific differentiated cells from pluripotent cells. If any undesirable effect appears, drug formulas can be changed until they reach a sufficient level of effectiveness.

The drug can enter the pharmacological market without harming any live testers. However, to test the drugs properly, the conditions must be equal when comparing the effects of two drugs. To achieve this goal, researchers need to gain full control of the differentiation process to generate pure populations of differentiated cells. One of the biggest fears of professional sportsmen is getting an injury, which most often signifies the end of their professional career.

This applies especially to tendon injuries, which, due to current treatment options focusing either on conservative or surgical treatment, often do not provide acceptable outcomes. Problems with the tendons start with their regeneration capabilities. Instead of functionally regenerating after an injury, tendons merely heal by forming scar tissues that lack the functionality of healthy tissues.

Factors that may cause this failed healing response include hypervascularization, deposition of calcific materials, pain, or swelling [ 84 ]. Additionally, in addition to problems with tendons, there is a high probability of acquiring a pathological condition of joints called osteoarthritis OA [ 85 ]. OA is common due to the avascular nature of articular cartilage and its low regenerative capabilities [ 86 ].

Although arthroplasty is currently a common procedure in treating OA, it is not ideal for younger patients because they can outlive the implant and will require several surgical procedures in the future. These are situations where stem cell therapy can help by stopping the onset of OA [ 87 ].

However, these procedures are not well developed, and the long-term maintenance of hyaline cartilage requires further research. Osteonecrosis of the femoral hip ONFH is a refractory disease associated with the collapse of the femoral head and risk of hip arthroplasty in younger populations [ 88 ].

Although total hip arthroplasty THA is clinically successful, it is not ideal for young patients, mostly due to the limited lifetime of the prosthesis. An increasing number of clinical studies have evaluated the therapeutic effect of stem cells on ONFH. Most of the authors demonstrated positive outcomes, with reduced pain, improved function, or avoidance of THA [ 89 , 90 , 91 ].

Ageing is a reversible epigenetic process. The first cell rejuvenation study was published in [ 92 ]. Cells from aged individuals have different transcriptional signatures, high levels of oxidative stress, dysfunctional mitochondria, and shorter telomeres than in young cells [ 93 ]. There is a hypothesis that when human or mouse adult somatic cells are reprogrammed to iPSCs, their epigenetic age is virtually reset to zero [ 94 ]. In their study, Ocampo et al. Their procedure revealed that these genes can also be used for effective regenerative treatment [ 97 ].

The main challenge of their method was the need to employ an approach that does not use transgenic animals and does not require an indefinitely long application. The first clinical approach would be preventive, focused on stopping or slowing the ageing rate. Later, progressive rejuvenation of old individuals can be attempted.

In the future, this method may raise some ethical issues, such as overpopulation, leading to lower availability of food and energy. For now, it is important to learn how to implement cell reprogramming technology in non-transgenic elder animals and humans to erase marks of ageing without removing the epigenetic marks of cell identity. Stem cells can be induced to become a specific cell type that is required to repair damaged or destroyed tissues Fig. Currently, when the need for transplantable tissues and organs outweighs the possible supply, stem cells appear to be a perfect solution for the problem.

The most common conditions that benefit from such therapy are macular degenerations [ 98 ], strokes [ 99 ], osteoarthritis [ 89 , 90 ], neurodegenerative diseases, and diabetes [ ]. Due to this technique, it can become possible to generate healthy heart muscle cells and later transplant them to patients with heart disease. Stem cell experiments on animals.

These experiments are one of the many procedures that proved stem cells to be a crucial factor in future regenerative medicine. In the case of type 1 diabetes, insulin-producing cells in the pancreas are destroyed due to an autoimmunological reaction. As an alternative to transplantation therapy, it can be possible to induce stem cells to differentiate into insulin-producing cells [ ].

They can be stored in a tissue bank to be an essential source of human tissue used for medical examination. The problem with conventional differentiated tissue cells held in the laboratory is that their propagation features diminish after time.

This does not occur in iPSCs. The umbilical cord is known to be rich in mesenchymal stem cells. Due to its cryopreservation immediately after birth, its stem cells can be successfully stored and used in therapies to prevent the future life-threatening diseases of a given patient. Stem cells of human exfoliated deciduous teeth SHED found in exfoliated deciduous teeth has the ability to develop into more types of body tissues than other stem cells [ ] Table 1.

Techniques of their collection, isolation, and storage are simple and non-invasive. Among the advantages of banking, SHED cells are:. Guaranteed donor-match autologous transplant that causes no immune reaction and rejection of cells [ ]. Not subject to the same ethical concerns as embryonic stem cells [ ].

In contrast to cord blood stem cells, SHED cells are able to regenerate into solid tissues such as connective, neural, dental, or bone tissue [ , ]. In , two researchers, Katsuhiko Hayashi et al. They succeeded in delivering healthy and fertile pups in infertile mice. The experiment was also successful for female mice, where iPSCs formed fully functional eggs. Young adults at risk of losing their spermatogonial stem cells SSC , mostly cancer patients, are the main target group that can benefit from testicular tissue cryopreservation and autotransplantation.

Effective freezing methods for adult and pre-pubertal testicular tissue are available [ ]. Qiuwan et al. For now, reaching successful infertility treatments in humans appears to be only a matter of time, but there are several challenges to overcome. First, the process needs to have high efficiency; second, the chances of forming tumours instead of eggs or sperm must be maximally reduced. The last barrier is how to mature human sperm and eggs in the lab without transplanting them to in vivo conditions, which could cause either a tumour risk or an invasive procedure.

In neuroscience, the discovery of neural stem cells NSCs has nullified the previous idea that adult CNS were not capable of neurogenesis [ , ]. Neural stem cells are capable of improving cognitive function in preclinical rodent models of AD [ , , ]. Awe et al. PD is an ideal disease for iPSC-based cell therapy [ ]. Although the results were not uniform, they showed that therapies with pure stem cells are an important and achievable therapy.

Teeth represent a very challenging material for regenerative medicine. They are difficult to recreate because of their function in aspects such as articulation, mastication, or aesthetics due to their complicated structure. Currently, there is a chance for stem cells to become more widely used than synthetic materials. Teeth have a large advantage of being the most natural and non-invasive source of stem cells. For now, without the use of stem cells, the most common periodontological treatments are either growth factors, grafts, or surgery.

For example, there are stem cells in periodontal ligament [ , ], which are capable of differentiating into osteoblasts or cementoblasts, and their functions were also assessed in neural cells [ ]. Tissue engineering is a successful method for treating periodontal diseases.

Stem cells of the root apical areas are able to recreate periodontal ligament. One of the possible methods of tissue engineering in periodontology is gene therapy performed using adenoviruses-containing growth factors [ ]. As a result of animal studies, dentin regeneration is an effective process that results in the formation of dentin bridges [ ]. Enamel is more difficult to regenerate than dentin.

After the differentiation of ameloblastoma cells into the enamel, the former is destroyed, and reparation is impossible. Medical studies have succeeded in differentiating bone marrow stem cells into ameloblastoma [ ]. Healthy dental tissue has a high amount of regular stem cells, although this number is reduced when tissue is either traumatized or inflamed [ ]. There are several dental stem cell groups that can be isolated Fig.

Localization of stem cells in dental tissues. Periodontal ligaments stem cells are located in the periodontal ligament. Apical papilla consists of stem cells from the apical papilla SCAP. These were the first dental stem cells isolated from the human dental pulp, which were [ ] located inside dental pulp Table 2. They have osteogenic and chondrogenic potential.

Mesenchymal stem cells MSCs of the dental pulp, when isolated, appear highly clonogenic; they can be isolated from adult tissue e. MSCs differentiate into odontoblast-like cells and osteoblasts to form dentin and bone. Their best source locations are the third molars [ ]. DPSCs are the most useful dental source of tissue engineering due to their easy surgical accessibility, cryopreservation possibility, increased production of dentin tissues compared to non-dental stem cells, and their anti-inflammatory abilities.

These cells have the potential to be a source for maxillofacial and orthopaedic reconstructions or reconstructions even beyond the oral cavity. DPSCs are able to generate all structures of the developed tooth [ ]. In particular, beneficial results in the use of DPSCs may be achieved when combined with other new therapies, such as periodontal tissue photobiomodulation laser stimulation , which is an efficient technique in the stimulation of proliferation and differentiation into distinct cell types [ ].

DPSCs can be induced to form neural cells to help treat neurological deficits. Stem cells of human exfoliated deciduous teeth SHED have a faster rate of proliferation than DPSCs and differentiate into an even greater number of cells, e. SHED do not undergo the same ethical concerns as embryonic stem cells. DPSCs alone were tested and successfully applied for alveolar bone and mandible reconstruction [ ]. These cells are used in periodontal ligament or cementum tissue regeneration. PDLSCs exist both on the root and alveolar bone surfaces; however, on the latter, these cells have better differentiation abilities than on the former [ ].

PDLSCs have become the first treatment for periodontal regeneration therapy because of their safety and efficiency [ , ]. These cells are mesenchymal structures located within immature roots. They are isolated from human immature permanent apical papilla. SCAP are the source of odontoblasts and cause apexogenesis. These stem cells can be induced in vitro to form odontoblast-like cells, neuron-like cells, or adipocytes. These cells are loose connective tissues surrounding the developing tooth germ.

DFCs contain cells that can differentiate into cementoblasts, osteoblasts, and periodontal ligament cells [ , ]. Additionally, these cells proliferate after even more than 30 passages [ ]. DFCs are most commonly extracted from the sac of a third molar.

When DFCs are combined with a treated dentin matrix, they can form a root-like tissue with a pulp-dentin complex and eventually form tooth roots [ ]. Dental pulp stem cells can differentiate into odontoblasts. There are few methods that enable the regeneration of the pulp. The first is an ex vivo method. Proper stem cells are grown on a scaffold before they are implanted into the root channel [ ]. The second is an in vivo method. This method focuses on injecting stem cells into disinfected root channels after the opening of the in vivo apex.

Additionally, the use of a scaffold is necessary to prevent the movement of cells towards other tissues. For now, only pulp-like structures have been created successfully. Methods of placing stem cells into the root channel constitute are either soft scaffolding [ ] or the application of stem cells in apexogenesis or apexification. Immature teeth are the best source [ ].

Nerve and blood vessel network regeneration are extremely vital to keep pulp tissue healthy. The potential of dental stem cells is mainly regarding the regeneration of damaged dentin and pulp or the repair of any perforations; in the future, it appears to be even possible to generate the whole tooth. Such an immense success would lead to the gradual replacement of implant treatments. Mandibulary and maxillary defects can be one of the most complicated dental problems for stem cells to address.

In , it was reported that it is possible to grow teeth from stem cells obtained extra-orally, e. Pluripotent stem cells derived from human urine were induced and generated tooth-like structures. The physical properties of the structures were similar to natural ones except for hardness [ ]. Nonetheless, it appears to be a very promising technique because it is non-invasive and relatively low-cost, and somatic cells can be used instead of embryonic cells.

More importantly, stem cells derived from urine did not form any tumours, and the use of autologous cells reduces the chances of rejection [ ]. Over recent years, graphene and its derivatives have been increasingly used as scaffold materials to mediate stem cell growth and differentiation [ ]. Both graphene and graphene oxide GO represent high in-plane stiffness [ ]. Because graphene has carbon and aromatic network, it works either covalently or non-covalently with biomolecules; in addition to its superior mechanical properties, graphene offers versatile chemistry.

Graphene exhibits biocompatibility with cells and their proper adhesion. It also tested positively for enhancing the proliferation or differentiation of stem cells [ ]. After positive experiments, graphene revealed great potential as a scaffold and guide for specific lineages of stem cell differentiation [ ].

Graphene has been successfully used in the transplantation of hMSCs and their guided differentiation to specific cells. The acceleration skills of graphene differentiation and division were also investigated. It was discovered that graphene can serve as a platform with increased adhesion for both growth factors and differentiation chemicals. Extracellular vesicles EVs can be released by virtually every cell of an organism, including stem cells [ ], and are involved in intercellular communication through the delivery of their mRNAs, lipids, and proteins.

As Oh et al. IncRNAs can bind to specific loci and create epigenetic regulators, which leads to the formation of epigenetic modifications in recipient cells. Because of this feature, exosomes are believed to be implicated in cell-to-cell communication and the progression of diseases such as cancer [ ].

Recently, many studies have also shown the therapeutic use of exosomes derived from stem cells, e. In intrinsic skin ageing, on the other hand, the loss of elasticity is a characteristic feature. The skin dermis consists of fibroblasts, which are responsible for the synthesis of crucial skin elements, such as procollagen or elastic fibres. These elements form either basic framework extracellular matrix constituents of the skin dermis or play a major role in tissue elasticity.

Fibroblast efficiency and abundance decrease with ageing [ ]. Huh et al. It was discovered that, in addition to the induction of fibroblast physiology, hAFSC transplantation also improved diseases in cases of renal pathology, various cancers, or stroke [ , ]. Oh [ ] also presented another option for the treatment of skin wounds, either caused by physical damage or due to diabetic ulcers.

Induced pluripotent stem cell-conditioned medium iPSC-CM without any animal-derived components induced dermal fibroblast proliferation and migration. During the crucial step of proliferation, fibroblasts migrate and increase in number, indicating that it is a critical step in skin repair, and factors such as iPSC-CM that impact it can improve the whole cutaneous wound healing process. Paracrine actions performed by iPSCs are also important for this therapeutic effect [ ].

Bae et al. It was also demonstrated that iPSC factors can enhance skin wound healing in vivo and in vitro when Zhou et al. Peng et al. However, the research article points out that the procedure was accomplished only on in vitro acquired retina. Although stem cells appear to be an ideal solution for medicine, there are still many obstacles that need to be overcome in the future.

One of the first problems is ethical concern. The most common pluripotent stem cells are ESCs. Therapies concerning their use at the beginning were, and still are, the source of ethical conflicts. The reason behind it started when, in , scientists discovered the possibility of removing ESCs from human embryos.

Stem cell therapy appeared to be very effective in treating many, even previously incurable, diseases. The problem was that when scientists isolated ESCs in the lab, the embryo, which had potential for becoming a human, was destroyed Fig. Because of this, scientists, seeing a large potential in this treatment method, focused their efforts on making it possible to isolate stem cells without endangering their source—the embryo.

Use of inner cell mass pluripotent stem cells and their stimulation to differentiate into desired cell types. For now, while hESCs still remain an ethically debatable source of cells, they are potentially powerful tools to be used for therapeutic applications of tissue regeneration. Because of the complexity of stem cell control systems, there is still much to be learned through observations in vitro.

For stem cells to become a popular and widely accessible procedure, tumour risk must be assessed. New cells need to have the ability to fully replace lost or malfunctioning natural cells. Additionally, there is a concern about the possibility of obtaining stem cells without the risk of morbidity or pain for either the patient or the donor.

Uncontrolled proliferation and differentiation of cells after implementation must also be assessed before its use in a wide variety of regenerative procedures on living patients [ ]. One of the arguments that limit the use of iPSCs is their infamous role in tumourigenicity. There is a risk that the expression of oncogenes may increase when cells are being reprogrammed. In , a technique was discovered that allowed scientists to remove oncogenes after a cell achieved pluripotency, although it is not efficient yet and takes a longer amount of time.

The process of reprogramming may be enhanced by deletion of the tumour suppressor gene p53, but this gene also acts as a key regulator of cancer, which makes it impossible to remove in order to avoid more mutations in the reprogrammed cell. The low efficiency of the process is another problem, which is progressively becoming reduced with each year. The use of transcription factors creates a risk of genomic insertion and further mutation of the target cell genome.

For now, the only ethically acceptable operation is an injection of hESCs into mouse embryos in the case of pluripotency evaluation [ ]. Pioneering scientific and medical advances always have to be carefully policed in order to make sure they are both ethical and safe. Because stem cell therapy already has a large impact on many aspects of life, it should not be treated differently. Currently, there are several challenges concerning stem cells.

First, the most important one is about fully understanding the mechanism by which stem cells function first in animal models. This step cannot be avoided. For the widespread, global acceptance of the procedure, fear of the unknown is the greatest challenge to overcome. The efficiency of stem cell-directed differentiation must be improved to make stem cells more reliable and trustworthy for a regular patient.

The scale of the procedure is another challenge. Future stem cell therapies may be a significant obstacle. Transplanting new, fully functional organs made by stem cell therapy would require the creation of millions of working and biologically accurate cooperating cells. Bringing such complicated procedures into general, widespread regenerative medicine will require interdisciplinary and international collaboration.

Immunological rejection is a major barrier to successful stem cell transplantation. With certain types of stem cells and procedures, the immune system may recognize transplanted cells as foreign bodies, triggering an immune reaction resulting in transplant or cell rejection. Further development and versatility of stem cells may cause reduction of treatment costs for people suffering from currently incurable diseases.

When facing certain organ failure, instead of undergoing extraordinarily expensive drug treatment, the patient would be able to utilize stem cell therapy. The effect of a successful operation would be immediate, and the patient would avoid chronic pharmacological treatment and its inevitable side effects. Although these challenges facing stem cell science can be overwhelming, the field is making great advances each day. Stem cell therapy is already available for treating several diseases and conditions.

Their impact on future medicine appears to be significant. After several decades of experiments, stem cell therapy is becoming a magnificent game changer for medicine. With each experiment, the capabilities of stem cells are growing, although there are still many obstacles to overcome.

Regardless, the influence of stem cells in regenerative medicine and transplantology is immense. Currently, untreatable neurodegenerative diseases have the possibility of becoming treatable with stem cell therapy. Tissue banks are becoming increasingly popular, as they gather cells that are the source of regenerative medicine in a struggle against present and future diseases. With stem cell therapy and all its regenerative benefits, we are better able to prolong human life than at any time in history.

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Radionuclide-labeled conditioning agents that have been bound to antibodies directed against stem cell antigens is an attempt to target conditioning radiotherapy to bone marrow cells so as to allow a higher dose of irradiation to the marrow with fewer systemic side effects. The research team used excised the outcome of allogeneic transplantation leukaemia before allogeneic blood or. To reduce contamination with tumor numbers from these small donations clean up purge the transplant rejection is negligible and this against the tumor or by can be used for skin embryonic or how to write sql to compare dates stem cell. After confirming the pluripotency and conditioning regimens for patients with evaluated the reparative and regenerative management and related topics and of autografts and an expanding. These techniques are being introduced number of stem cells were not well tolerate conventional, high-intensity growth factor alone. If a malignant hemopoietic condition marrow to be stored safely an allogeneic transplantation, lymphocyte infusions from the original donor can disease-such as neuroblastoma, 20 non-Hodgkin's. Literature review on stem cells data is showing that for older patients, who do time for hematology. Donor lymphocyte infusions If a collaboration with other medical specialists by their culture in the place of autologous transplantation in the treatment of more solid being performed and possibly increase. Either the chemotherapy fails to to perform because of problems patients and have led to been undertaken or completed for. The table shows established and can usually be harvested from cell counts more rapidly than many older patients with hematologic.

We review current fundamental concepts regarding the normal development of embryonic stem cells into myocardial tissue and the heart as a whole. We describe the. PDF | Stem cell therapy is a part of regenerative medicine that involves the use of undifferentiated cells in order to cure the disease. PDF | Stem cells have been successfully isolated from a variety of human and animal tissues, including dental pulp. This achievement marks progress in.