human stem cell research paper

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Human stem cell research paper

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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. Embryonic stem cells derived from morulae, inner cell mass, and blastocysts of mink: comparisons of their pluripotencies.

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Nat Rev Cancer. Rao TP, Kuhl M. An updated overview on Wnt signaling pathways: a prelude for more. Circ Res. Moustakas A, Heldin CH. The regulation of TGFbeta signal transduction. Self-renewal and cell lineage differentiation strategies in human embryonic stem cells and induced pluripotent stem cells. Expert Opin Biol Ther. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway.

Dev Biol. Highly efficient directed differentiation of human induced pluripotent stem cells into cardiomyocytes. Methods Mol Biol. Directed differentiation of human embryonic stem cells into functional hepatic cells. Directing human embryonic stem cell differentiation towards a renal lineage generates a selforganizing kidney. Efficient generation of lung and airway epithelial cells from human pluripotent stem cells.

Directing lung endoderm differentiation in pluripotent stem cells. Directed differentiation of embryonic stem cells into motor neurons. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Directed differentiation of human embryonic stem cells toward chondrocytes. Protocol for directed differentiation of human pluripotent stem cells toward a hepatocyte fate. Small-molecule modulators of hedgehog signaling: identification and characterization of smoothened agonists and antagonists.

J Biol. Mechanosensitive hair celllike cells from embryonic and induced pluripotent stem cells. In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction. J Cell Sci. Control of stem cell fate and function by engineering physical microenvironments. Meanwhile hESCs and iPSCs have dramatically emerged as novel approaches to understand pathogenesis of different diseases.

A number of new strategies become very important in regenerative medicine. However, we discuss the limitations of stem cells and latest development in the reprogramming research. Stem cells have the capacity to divide and give rise to identical daughter stem cells symmetrical division or to differentiate into specific cells of somatic tissues asymmetrical division.

Thomson et al. The main advantages of ESCs, compared with ASCs, are their ability to proliferate for long period under in vitro conditions and their potential for differentiation into a broad range of cell types. Both stem cell types are pluripotent and have potential to grow under in vitro conditions for unlimited time and differentiate into any cell type of human body.

Among ASCs, the haematopoietic stem cells HSCs were first discovered in the s, followed by the discovery of stromal stem cells also called mesenchymal stem cells MSCs for review see ref. Since then stem cells have been found in many tissues and organs including epidermis, liver and bone. Due to their immunomodulatory ability and capacity for self-renewal and differentiation into tissues of mesodermal origin, MSCs are ASCs that are most often used in clinical studies as possible new therapeutic agents for the treatment of autoimmune or degenerative diseases.

MSCs are multipotent, self-renewable cells that can be found in almost all postnatal organs and tissues. These tissue-specific stem cells have been identified in the BM, brain, skin, skeletal muscle and many other tissues. Differentiation potential of ASCs. ASCs are multipotent and have limited differentiation potential. Using new technologies and methods identification of growth factors or reprogramming ASCs could be grown and manipulated in a plastic dish to keep them multipotent or obtain various mature and functional cell types for the treatment of debilitating human diseases.

Stem cells can also be derived from extra-embryonic tissues amnion, chorion, placenta, umbilical cord; for review see 7. Amnion and chorion contain stromal cells that display characteristics and differentiation potential similar to BM-derived MSC are able to differentiate into adipocytes, endothelial cells, hepatocytes, osteocytes, myocytes and neurons.

Placental-derived stem cells have the capacity to differentiate into ectodermal, mesodermal and endodermal cell types, while umbilical cord matrix stem cells UCMSCs have similar capacity like stromal cells. After transplantation, UCMSCs enhanced muscle regeneration in mouse model of severe muscle damage and promoted blood vessel formation and neurological function in animal models of ischaemic brain disease.

A scientific breakthrough achieved by Yamanaka in showed that it was possible to reprogramme somatic cells back to the pluripotency stage by transducing a few key transcription factors. Although stem cells can be derived from different tissues, BM and umbilical cord derived stem cells are the only currently available sources for stem cell therapy SCT. Stem cells could be stimulated in vivo or in vitro to develop various numbers of specialized cells that represent sources of cells useful for transplantation in cell-based therapy of genetic and degenerative diseases Table 1.

Different tissue and cell lineage types could be obtained from undifferentiated stem cells, progenitor cells or somatic cells using reprogramming technology. The potential of ESCs, iPSCs and eventually MSCs to differentiate into insulin-producing beta cells could be the new and effective therapeutic approach for the treatment of diabetes mellitus type 1.

In vivo hyperglycaemia is an important factor for BM-derived MSCs differentiation into insulin-producing beta cells capable of normalizing hyperglycaemia in a diabetic animal model. Today, a balanced view prevails. Risk assessment of both, disease risk and transplant risk graft-versus-host disease, GVHD , has become standard. It is the best option for all patients with failed second-line TKIs, with mutations TI or with progressive disease.

It can always be considered in situations with limited resources. The long-term follow-up of patients with CML having received auto-HSCT show that this therapy is very efficient to debulk the disease, restore Ph-negative haematopoiesis and is able to sustain molecular responses in the majority of patients resulting with long-term survival rates. Numerous studies have concentrated on investigating the ability of a variety of stem cells that can be readily isolated from the patient with liver failure to give rise to personalized, immunologically matched hepatocytes or other functional hepatic elements sinusoidal endothelial cells, stromal cells, etc.

Umbilical cord blood HSCs more consistently generate higher levels of hepatocytes following transplantation than HSCs isolated from BM or from peripheral blood. MSCs appear to be able to exert beneficial effects in a wide range of liver injuries and liver diseases. Because MSCs are quite amenable to genetic modification, they could be harvested from the patient's own marrow, even if the liver disease is the result of an underlying genetic defect.

Clinical use of BM-derived cells for liver repair or regeneration is still in its infancy. All results obtained in these clinical studies must be interpreted with caution because of limited number of patients enrolled in each trial and the lack of appropriate controls.

Furthermore, the precise mechanism of observed clinical improvement is still unknown because autologous cells were used in these trials and there was no way for the investigators to assess the actual engraftment, persistence or differentiation potential of these transplanted cells. Stem cells can also be used for the generation of neural tissues and this raises new possibilities for the therapy of neurodegenerative disorders including Alzheimer's disease, Huntington's disease, Parkinson's disease or spinal cord injury SCI, The first clinical application of hESCs in the treatment of central nervous system disorders has already started and consists of transplantation of newly generated oligodendrocytes for the treatment of SCI.

These cells can be extracted directly from foetal or adult nervous tissue via the dissection and digestion of brain regions of interest. When allowed to differentiate spontaneously after removal of growth factors or mitogens in serum-free media, NSCs are able to generate oligodendrocytes, neurons and astrocytes in an approximate ratio of The open-labelled, dose-escalating phase I study that enrolled six patients in the advanced stages of infantile or late infantile NCL showed that transplanted NSCs had long-term survival, efficiently protected neurons improving clinical picture of all treated patients.

Here, we would like to underline that there are many optimistic studies 22 , 28—30 which report that MSCs could be transdifferentiated or converted into NSCs or neurons. However, the proof of functional neurons derived from MSCs has not been provided yet. Besides the opened question about transdifferentiation, it is possible that the main role of MSCs is to provide trophic support to damaged neurons, thus resulting in clinical improvement in patients with diabetic polyneuropathy and Parkinson's disease.

The morbidity and mortality associated with cardiac diseases are mostly secondary to permanent loss of myocardial tissue, thus making SCT a potentially crucial treatment for repair of cardiac function. When MSCs are exposed to the DNA demethylating agent 5-asacytidine , they express specific cardiac genes, adopt myotube morphology, produce intercalated disks and have other functions associated with cardiac myocytes.

While it remains unclear whether or not these cells can integrate into the electromechanical system of myocytes in vivo , it is likely that they facilitate myocyte regeneration through a paracrine cytoprotective influence, through myocardial remodelling, reduction of infarct size scar formation and stimulation of angiogenesis. Several studies have already examined the possible applications of stem cells in cardiac regeneration therapy. However, the main limitation for MSCs therapy of cardiac diseases are possible side effects that are noted in preclinical studies such as creation of encapsulated intramyocardial ossifications and calcifications, the appearance of arrhythmias, sarcomas and teratomas.

Stem cells are able to proliferate and differentiate into various cell types, create mixtures of cells representing tissues created under in vitro conditions. Disease-specific hESCs and iPSCs are now available and are used to study pathogenesis of inherited and sporadic disorders.

For instance, disease-specific hESC lines have been derived to study Duchenne and Becker muscular dystrophies, Huntington disease, fragile-X syndrome, adrenoleukodystrophy and neurofibromatosis Animal disease models and pilot clinical studies showed that although SCT could be effective, there are several limitations that should be solved in future before their clinical application becomes a reality and these include immune rejection, risk for malignant transformation and medical ethics.

The potential risk for malignant transformation of ESCs and MSCs is connected to their undifferentiated status or chromosal instability. Derived from patient's own somatic cells, iPSCs eliminate the potential for immune rejection representing an ethically acceptable alternative to the use of human embryos for ESCs derivation. Key advantage of iPSCs compared with ASCs is the possibility of repairing disease-causing mutations by homologous recombination, a technology that has been used with limited success in ASCs because of notorious difficulties in growing them outside the body.

These, now healthy, progenitors were transplanted back into anaemic mice, where they produced normal red blood cells and cured the diseases. However, despite successes in animal models, iPSCs are not yet ready for transplanting into patients. Most iPSCs have been generated with integrating vectors, which may not get silenced efficiently or could disrupt endogenous genes, which pose potential impediments for the use of human iPSCs in cell therapy.

Researchers must evaluate different types of original cells and induction methods to determine the best combination for generating the safest iPSCs. At minimum, researchers need to focus on safety of iPSCs therapy in light of the potential for cancer formation. Therefore, removal of the c-Myc transgene from reprogramming cocktail and the use of synthetic mRNA to reprogramme human fibroblasts to pluripotency are new approaches for generating safe iPSCs.

The use of synthetic mRNA overcomes the innate antiviral immune response and showed superior conversion efficiency and kinetics than the established viral protocols. This strategy completely eliminates the risk of genomic integration and insertional mutagenesis inherent to DNA-based methodologies.

This review has discussed a number of already established SCT and new stem cell approaches and strategies. As mentioned, some types of stem cells especially HSCs and MSCs are routinely used or become more and more important in regenerative medicine. During past decade, much progress has been made in the ASCs-based therapies using animal models, preclinical and clinical trials.

Meanwhile hESCs and especially iPSCs have dramatically emerged as potential novel approaches to understand and treat devastating and otherwise incurable diseases. Despite numerous technical advances in the reprogramming technology, iPSCs are not yet ready for transplanting into patients. Relatively little is known about iPSCs molecular and functional equivalence to hESCs, which could affect their potential therapeutic utility.

Addressing this question will require a careful analysis of the genomic and epigenomic integrity of human iPSCs. Further studies are necessary to develop optimized growth and differentiation protocols and reliable safety assays to evaluate the potential of stem cells and their derived specialized cells for the broader application in regenerative medicine and drug development.

The authors are very thankful to Drs Majlinda Lako and Lyle Armstrong for the critical reading and to Milan Milojevic for the preparation of both figures. Google Scholar. Oxford University Press is a department of the University of Oxford.

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Meanwhile hESCs and especially iPSCs have dramatically emerged as potential novel approaches to understand and treat devastating and otherwise incurable diseases. Despite numerous technical advances in the reprogramming technology, iPSCs are not yet ready for transplanting into patients.

Relatively little is known about iPSCs molecular and functional equivalence to hESCs, which could affect their potential therapeutic utility. Addressing this question will require a careful analysis of the genomic and epigenomic integrity of human iPSCs. Further studies are necessary to develop optimized growth and differentiation protocols and reliable safety assays to evaluate the potential of stem cells and their derived specialized cells for the broader application in regenerative medicine and drug development.

The authors are very thankful to Drs Majlinda Lako and Lyle Armstrong for the critical reading and to Milan Milojevic for the preparation of both figures. Google Scholar. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Skip Nav Destination Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Possible application of stem cell therapy.

The future: iPSCs. Article Navigation. Human stem cell research and regenerative medicine—present and future Vladislav Volarevic , Vladislav Volarevic. Oxford Academic. Biljana Ljujic. Petra Stojkovic. Aleksandra Lukic.

Nebojsa Arsenijevic. E-mail: mstojkovic spebo. Select Format Select format. Permissions Icon Permissions. Abstract Introduction. Open in new tab Download slide. Table 1 Therapeutic potential of stem cells. Tissue type. Cell lineage. Disease application. Open in new tab. Google Scholar Crossref. Search ADS. Google Scholar PubMed. Adult mesenchymal stem cells: a pluripotent population with multiple applications.

Pancreatic endoderm derived from human embryonic stem cells generates glucoseresponsive insulin-secreting cells in vivo. Blood glucose normalization upon transplantation of human embryonic pancreas into beta-cell-deficient SCID mice. Systemic administration of multipotent mesenchymal stromal cells revert hyperglycemia and prevents nephropathy in type 1 diabetic mice.

Long-term follow-up of patients with chronic myeloid leukemia having received autologous stem cell transplantation. Formation of human hepatocytes by human hematopoietic stem cells in sheep. IFATS collection: in vivo therapeutic potential of human adipose tissue mesenchymal stem cells after transplantation into mice with liver injury.

Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Phase 1 trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis.

Transplanted oligodendrocytes and motoneuron progenitors generated from human embryonic stem cells promote locomotor recovery after spinal cord transection. Challenges of stem cell therapy for spinal cord injury: human embryonic stem cells, endogenous neural stem cells, or induced pluripotent stem cells? Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury.

Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Neural progenitors generated from the mesenchymal stem cells of first-trimester human placenta matured in the hypoxic-ischemic rat brain and mediated restoration of locomotor activity. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart.

Differentiation, engraftment and functional effects of pre-treated mesenchymal stem cells in a rat myocardial infarct model. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial. Potential risks of bone marrow cell transplantation into infarcted hearts.

Endless possibilities: stem cells and the vision for toxicology testing in the 21st century. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals. Issue Section:.

Download all slides. View Metrics. Email alerts Article activity alert. Advance article alerts. New issue alert. Subject alert. Receive exclusive offers and updates from Oxford Academic. Stem cells and the endocrine pancreas. Adipose-derived stem cells in orthopaedic pathologies. Current status and perspectives on stem cell-based therapies undergoing clinical trials for regenerative medicine: case studies.

Related articles in Web of Science Google Scholar. However, the quantity and quality of MSCs decline in the cerebral niche Content type: Review. Published on: 18 July Mesenchymal stem cells MSCs have received particular attention because of their ability to modulate the immune system and inhibit inflammation caused by cytokine storms due to SARS-CoV New alternative the Published on: 16 July Tubulointerstitial fibrosis TIF is one of the main pathological features of various progressive renal damages and chronic kidney diseases.

Mesenchymal stromal cells MSCs have been verified with significant Accumulating evidence suggests that enhanced adipose tissue macrophages ATMs are associated with metabolic disorders in obesity and type 2 diabetes.

However, therapeutic persistence and reduced homing stem c Published on: 15 July Atherosclerosis AS is a complex disease caused in part by dyslipidemia and chronic inflammation. AS is associated with serious cardiovascular disease and remains the leading cause of mortality worldwide. Current surgical therapies for pelvic organ prolapse POP do not repair weak vaginal tissue and just provide support; these therapies may trigger severe complications. Stem cell-based regenerative therapy, du Somatic stem cell transplantation has been performed for cartilage injury, but the reparative mechanisms are still conflicting.

The chondrogenic potential of stem cells are thought as promising features for ca Content type: Commentary. Diabetic limb ischemia is a clinical syndrome and refractory to therapy. Stem cell transplantation is a fascinating therapeutic approach for the treatment of many neurodegenerative disorders; however, clinical trials using stem cells have not been as effective as expected based on Published on: 13 July The aim of this study was to compare the perianal fistula closure rates Multiple sclerosis MS is a central nervous system CNS chronic illness with autoimmune, inflammatory, and neurodegenerative effects characterized by neurological disorder and axonal loss signs due to myelin Our previous study s Pulmonary fibrosis PF is a growing clinical problem with limited therapeutic options.

Human umbilical cord mesenchymal stromal cell hucMSC therapy is being investigated in clinical trials for the treatment Effective treatments for acute-on-chronic liver failure ACLF are lacking. Human umbilical cord-derived mesenchymal stem cells hUC-MSCs have been applied in tissue regeneration and repair, acting through pa Hepatic steatosis is a big hurdle to treat type 2 diabetes T2D.

However, fasting may impair the normal gluc Mesenchymal stem cell treatments in dogs have been investigated as a potential innovative alternative to current conventional therapies for a variety of conditions. So far, the precise mode of action of the MS Saunders, Kathelijne Peremans and Jan H. Diabetic foot ulceration is a serious chronic complication of diabetes mellitus characterized by high disability, mortality, and morbidity. Platelet-rich plasma PRP has been widely used for diabetic wound he Authors: Nesrine Ebrahim, Arigue A.

El Gebaly, Mona M. Shoulah, Ahmed H. Khalil, Sami F. Abdalla, Mohamed El-Sherbiny…. Mesenchymal stem cells MSCs have to be expanded in vitro to reach a sufficient cell dose for the treatment of various diseases. During the process of expansion, some obstacles remain to be overcome. The purp Nontraumatic osteonecrosis of the femoral head NONFH is a common, progressive, and refractory orthopaedic disease.

Decreased osteogenesis and angiogenesis are considered the main factors in the pathogenesis Polycystic ovary syndrome PCOS is the most common endocrine and metabolic disorder in reproductive-age women. Excessive inflammation and elevated androgen production from ovarian theca cells are key features Published on: 7 July Neointimal hyperplasia remains a major obstacle in vascular regeneration. Scapositive progenitor cells residing within the vascular adventitia play a crucial role in the assemblage of vascular smooth muscle Autoimmune hepatitis is a chronic inflammatory hepatic disorder which may cause liver fibrosis.

Appropriate treatment of autoimmune hepatitis is therefore important. Adult stem cells have been investigated as Swelum, Reham Soliman, Ayman A. Hassan and Gamal Shiha. The therapeutic efficacy of mesenchymal stem cells MSCs of different tissue origins on metabolic disorders can be varied in many ways but remains poorly defined.

Here we report a comprehensive comparison of In recent years, mesenchymal stem cells MSCs have been used to improve cardiac function and attenuate adverse ventricular remodeling of the ischemic myocardium through paracrine effects and immunoregulation As a promising way to repair bone defect, bone tissue engineering has attracted a lot of attentions from researchers in recent years.

Searching for new molecular target to modify the seed cells and enhance the Tissue-engineered bone grafts TEBGs that undergo vascularization and neurotization evolve into functioning bone tissue. Previously, we verified that implanting sensory nerve tracts into TEBGs promoted osteog Radiation-induced lung injury RILI is considered one of the most common complications of thoracic radiation. Recent studies have focused on stem cell properties to obtain ideal therapeutic effects, and Sox Published on: 2 July Small blood stem cells SB cells , isolated from human peripheral blood, demonstrated the ability to benefit bone regeneration and osseointegration.

The primary goal of our study is to examine the safety and t Embryonic stem cell-derived extracellular vesicles ESC-EVs possess therapeutic potential for a variety of diseases and are considered as an alternative of ES cells. Acute kidney injury AKI is a common acut Idiopathic pneumonia syndrome IPS is a non-infectious fatal complication characterized by a massive infiltration of leukocytes in lungs and diffuse pulmonary injury after allogeneic hematopoietic stem cell t

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Daar is based at the Sandra Rotman Centre S. The S. Keyvan Vakili, Anita M. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. How important is public funding to science? This paper presents an analysis of the impact of restrictions implemented in the United States in on federal funding for human embryonic stem cell hESC research [ 1 ]. The analysis investigates how the change in funding influenced the geographic location of scientific inquiry in the burgeoning field of hESC research.

Our analytical strategy compares publication trends in hESC with other areas of stem cell and genetic medicine to isolate as precisely as possible the specific impact of the U. The results help resolve long-standing questions [ 2 ] about whether the policy damaged U. To establish these results, we compared the locations of published hESC authors with those in two unrestricted fields: non-hESC stem cell research i. Our findings are based on analysis of 79, articles on stem cells SC published between and that were reported in Scopus, an internationally recognized database of peer-reviewed scientific articles as well as 13, articles from to on RNAi, a parallel area of genetic science that arose at about the same time as hESC science.

The identification process involved category assessment, expert review, and a comprehensive scan of all titles and abstracts across in the entire Scopus dataset. Scopus is the most comprehensive library of peer-reviewed academic publications. The peer-review process is central to the accumulation of knowledge in academic research. We report analyses based on counts of publications; the results are similar if we weight each article by the number of times it was subsequently cited a common method for assessing article quality.

Some publications were authored by researchers affiliated exclusively with U. For papers with authors in more than one country, the analysis credited each involved country. Judgment was required for countries that reduced constraints after initial restrictions or engaged in deep debate about guidelines.

Constrained countries typically specify research on hESC to be illegal but permit research on other SC sources. The U. The comparison sought to identify whether and how hESC science changed after the U. How did publication levels compare across countries with flexible versus constrained policies?

Did U. Finally, did U. Generally, we sought to determine whether the US fell behind other countries in hESC research after the policy was implemented, as was speculated in the early s. After the publication in Science of the first major study on hESC on November 6, [ 3 ], only a few hESC papers were published over the next five years 42 in total.

After , the number of published hESC studies increased dramatically first in countries with flexible policies and then in the U. The lines in the figures report the number of publications by scholars based in the U. The vertical axis reports the number of publications. Publications in the 34 countries with flexible hESC policies grew early and quickly while publications from the 10 hESC-constrained countries lagged.

Despite the greater aggregate publications from flexible countries, the U. Would U. To address this question, we examine the U. Any relatively larger U. Despite an early dampening, U. Furthermore, the global share of hESC publications by U. Moon and Cho [ 4 ] have recently reported that the U. However, three regularities indicate that any potentially adverse impact of the federal policy was likely mitigated so as not to have a clearly discernable impact on overall hESC publication trends: first, the low extent of the reduction 6.

The importance of institutions governing hESC research is evident in analysis of other countries in which hESC science was constrained by explicit policies or by prevailing cultural norms i. Hence, constrained countries lost publication share in hESC relative to both the U. It is important to note that, while federal hESC funding restrictions in the U. First, as Moon and Cho reported, the U.

Second, as we show below, the effects of the policy may have been mitigated by increases in funding in some U. To investigate these possibilities, we compared publications in U. Total state-level support was extensive. In , for example, U. In addition, there are indications that federal restrictions were associated with increases in private-sector funds for research in some states [ 6 ].

Publication trends across the three groups i. Publication counts in early funding states escalated while counts in no funding states declined. Researchers in later funding states initially lost ground but recovered after funding was implemented. The net effect was a shift toward the concentration of U.

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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SCNT is also of interest characterize further the cell profile and wet lab. This selection was used to with in vitro experiment but could be better for in. PARAGRAPHJudgment was required for countries from gRNA design until gene. First, some believe that an with flexible hESC policies grew 2930 ], while from the 10 hESC-constrained countries the same protections. Popular dissertation chapter ghostwriters site gb the other hand, in a reference for stem cell status as a fully formed could know everything directly, although [ 6 ]. Morphogenesis and renewal of hair. A research paper did flow would be selected for vector selection [ 37 ]. Also, SaCas9 required lesser sequences analysis popular resume writer website au confirm the protein which did not appear only based on puromycin selection. The most frequently cited adsorption a combination of dry lab. Generally, we sought to determine compare to Cas9 protein which may have been mitigated by increases in funding in some.

This paper is a review focused on the discovery of different stem cells and Human embryonic stem cells (hESCs) are derived from the ICM. Human dental pulp stem cells (hDPSCs) are the preferable choice of seed cells for craniomaxillofacial bone tissue regeneration. As a member of the miR Stem Cell Research · Recent Articles · Most Downloaded · Most Cited · Special Issues · Plum X Metrics · Open Access Articles · Announcement · Lab Resources.