Cells from the early embryo are pluripotent. Multipotent : These cells can differentiate into a closely related family of cells. Adult hematopoietic stem cells, for example, can become red and white blood cells or platelets. Oligopotent : These can differentiate into a few different cell types. Adult lymphoid or myeloid stem cells can do this. Unipotent : These can only produce cells of one kind, which is their own type.
However, they are still stem cells because they can renew themselves. Examples include adult muscle stem cells. Embryonic stem cells are considered pluripotent instead of totipotent because they cannot become part of the extra-embryonic membranes or the placenta. First, with the right stimulation, many stem cells can take on the role of any type of cell, and they can regenerate damaged tissue, under the right conditions. This potential could save lives or repair wounds and tissue damage in people after an illness or injury.
Scientists see many possible uses for stem cells. Until now, a person who needed a new kidney, for example, had to wait for a donor and then undergo a transplant. There is a shortage of donor organs but, by instructing stem cells to differentiate in a certain way, scientists could use them to grow a specific tissue type or organ. They can then repair a severe burn or another injury by grafting this tissue onto the damaged skin, and new skin will grow back.
In , a team of researchers from Massachusetts General Hospital reported in PNAS Early Edition that they had created blood vessels in laboratory mice, using human stem cells. Within 2 weeks of implanting the stem cells, networks of blood-perfused vessels had formed. The quality of these new blood vessels was as good as the nearby natural ones.
The authors hoped that this type of technique could eventually help to treat people with cardiovascular and vascular diseases. Scientists could use stem cells to replenish the damaged brain tissue. This could bring back the specialized brain cells that stop the uncontrolled muscle movements. Researchers have already tried differentiating embryonic stem cells into these types of cells, so treatments are promising.
Scientists hope one day to be able to develop healthy heart cells in a laboratory that they can transplant into people with heart disease.
Similarly, people with type I diabetes could receive pancreatic cells to replace the insulin-producing cells that their own immune systems have lost or destroyed. The only current therapy is a pancreatic transplant, and very few pancreases are available for transplant.
Doctors now routinely use adult hematopoietic stem cells to treat diseases, such as leukemia , sickle cell anemia , and other immunodeficiency problems. Hematopoietic stem cells occur in blood and bone marrow and can produce all blood cell types, including red blood cells that carry oxygen and white blood cells that fight disease.
People can donate stem cells to help a loved one, or possibly for their own use in the future. Bone marrow : These cells are taken under a general anesthetic, usually from the hip or pelvic bone. Technicians then isolate the stem cells from the bone marrow for storage or donation. Peripheral stem cells : A person receives several injections that cause their bone marrow to release stem cells into the blood.
Next, blood is removed from the body, a machine separates out the stem cells, and doctors return the blood to the body. Umbilical cord blood : Stem cells can be harvested from the umbilical cord after delivery, with no harm to the baby.
Some people donate the cord blood, and others store it. For example, scientists have found that switching a particular gene on or off can cause it to differentiate.
Knowing this is helping them to investigate which genes and mutations cause which effects. Armed with this knowledge, they may be able to discover what causes a wide range of illnesses and conditions, some of which do not yet have a cure. Abnormal cell division and differentiation are responsible for conditions that include cancer and congenital disabilities that stem from birth. Knowing what causes the cells to divide in the wrong way could lead to a cure.
Stem cells can also help in the development of new drugs. Instead of testing drugs on human volunteers, scientists can assess how a drug affects normal, healthy tissue by testing it on tissue grown from stem cells. There has been some controversy about stem cell research.
This mainly relates to work on embryonic stem cells. The argument against using embryonic stem cells is that it destroys a human blastocyst, and the fertilized egg cannot develop into a person. Nowadays, researchers are looking for ways to create or use stem cells that do not involve embryos.
Stem cell research often involves inserting human cells into animals, such as mice or rats. Some people argue that this could create an organism that is part human. Mesenchymal stem cell therapy can be deployed systemically via IV or injected locally to target specific sites, depending on patient needs.
Stem cell therapy is a form of regenerative medicine designed to repair damaged cells within the body by reducing inflammation and modulating the immune system. This phenomenon makes stem cell therapy a viable treatment option for a variety of medical conditions.
Stem cell therapies have been used to treat autoimmune, inflammatory, neurological, orthopedic conditions and traumatic injuries with studies conducted on use for Crohn's disease, Multiple Sclerosis, Lupus, COPD, Parkinson's, ALS, Stroke recovery and more. While stem cell therapy does not necessarily provide a cure for these conditions, the premise is to allow the body to heal itself well enough to mitigate the symptoms of the conditions for long periods.
In many cases, this effect can substantially increase the quality of life for patients as well as delay disease progression. Stem cells can be obtained from many different sources. These include adipose fat tissue , umbilical cord tissue, placental tissue, umbilical cord blood, or bone marrow. Stem cells can be administered in a variety of fashions; IV Stem Cell Therapy Intravenous administration , Intrathecal directly into the spinal canal , Site injections into problem areas Knee, hips, hands, etc.
Mesenchymal stem cells utilize their self-renewal, immunomodulatory, anti-inflammatory, signaling, and differentiation properties to influence positive change within the body.
Mesenchymal stem cells MSCs also have the capacity to self-renew by dividing and developing into multiple specialized cell types present in a specific tissue or organ. Mesenchymal stem cells are adult stem cells, meaning they present no ethical concerns, MSCs are not sourced from embryonic material.
The therapeutic uses of stem cells as a potential therapy for a variety of diseases has been immensely explored, the number of clinical trials conducted with Mesenchymal Stem Cells has increased exponentially over the past few years.
Stem cells have a unique, intrinsic property that attracts them to inflammation in the body. Studies have shown that stem cells can regenerate damaged or diseased tissues, reduce inflammation and modulate the immune system promoting better health and quality of life.
Mesenchymal stem cells do this by influencing tissue repair via paracrine effects cell signaling in order to change the behaviour of existing cells or direct cell-to-cell contact. Stem cells are the body's raw materials — cells from which all other cells with specialized functions are created. Mesenchymal stem cells are adult stem cells that have self-renewal, immunomodulatory, anti-inflammatory, signaling, and differentiation properties.
Mesenchymal stem cells MSCs , self renewal capacity is characterized by their ability to divide and develop into multiple specialized cell types present in a specific tissue or organ. Mesenchymal stem cells MSCs can be sourced from a variety of tissue including adipose tissue fat , bone marrow, umbilical cord tissue, blood, liver, dental pulp, and skin. MSCs are widely used in the treatment of various diseases due to their self-renewable, differentiation, anti-inflammatory, and immunomodulatory properties.
In-vitro performed in a laboratory setting and in-vivo taking place in a living organism studies have supported the understanding mechanisms, safety, and efficacy of MSC therapy in clinical applications. According to Biehl et al. A stem cell can become many different cell types in the human body.
The process of stem cells maturing into new types of cells is called differentiation. Stem cells are also self-replicating; this ability allows the cells to multiply into identical copies of themselves. For example, if stem cells were used to treat a neurological injury, cells administered during treatment could become nerve cells, and then replicate to create exponentially more nerve cells on their own.
This ability to duplicate drastically increases the effectiveness of stem cell treatments over time. Mesenchymal stem cells are multipotent stem cells that can self-renew and differentiate into different cell types. According to a study conducted by Almalki et al. Mesenchymal stem cells contribute to tissue regeneration and differentiation, including the maintenance of homeostasis and function, adaptation to altered metabolic or environmental requirements, and the repair of damaged tissue.
Stem cell numbers and effectiveness begin to decrease as we age exponentially. For example, stem cells from a person in their twenties are not nearly as high quality as the brand new cells sourced from umbilical cord tissue. Stem cells do not necessarily provide a cure for these conditions. The premise is allowing the body to heal itself well enough to mitigate the symptoms of the conditions for long periods. In many cases, this alone allows for a substantial increase in quality of life for patients.
Cord-tissue derived mesenchymal stem cells do not have any risk of rejection within the body. There are no blood products associated with them either, removing the need for a donor match; they are universally accepted. These cells seek out inflammation in the body and begin to heal the damaged tissue. Mesenchymal cord tissue-derived stem cells have been administered thousands of times at clinics around the world without instances of rejection graft vs.
Although karyology is a crucial procedure in stem cell quality control, the single nucleotide polymorphism SNP array, discussed later, has approximately 50 times higher resolution. Viral testing—When assessing the quality of stem cells, all tests for harmful human adventitious agents must be performed e. This procedure must be performed in the case of non-xeno-free culture agents. Bacteriology—Bacterial or fungal sterility tests can be divided into culture- or broth-based tests. All the procedures must be recommended by pharmacopoeia for the jurisdiction in which the work is performed.
Single nucleotide polymorphism arrays—This procedure is a type of DNA microarray that detects population polymorphisms by enabling the detection of subchromosomal changes and the copy-neutral loss of heterozygosity, as well as an indication of cellular transformation. The SNP assay consists of three components. The first is labelling fragmented nucleic acid sequences with fluorescent dyes. The second is an array that contains immobilized allele-specific oligonucleotide ASO probes.
The last component detects, records, and eventually interprets the signal. Flow cytometry—This is a technique that utilizes light to count and profile cells in a heterogeneous fluid mixture. It allows researchers to accurately and rapidly collect data from heterogeneous fluid mixtures with live cells.
Cells are passed through a narrow channel one by one. During light illumination, sensors detect light emitted or refracted from the cells.
The last step is data analysis, compilation and integration into a comprehensive picture of the sample. Phenotypic pluripotency assays—Recognizing undifferentiated cells is crucial in successful stem cell therapy. Among other characteristics, stem cells appear to have a distinct morphology with a high nucleus to cytoplasm ratio and a prominent nucleolus. Cells appear to be flat with defined borders, in contrast to differentiating colonies, which appear as loosely located cells with rough borders [ 5 ].
It is important that images of ideal and poor quality colonies for each cell line are kept in laboratories, so whenever there is doubt about the quality of culture, it can always be checked according to the representative image.
Embryoid body formation or directed differentiation of monolayer cultures to produce cell types representative of all three embryonic germ layers must be performed. It is important to note that colonies cultured under different conditions may have different morphologies [ 6 ].
Histone modification and DNA methylation—Quality control can be achieved by using epigenetic analysis tools such as histone modification or DNA methylation. When stem cells differentiate, the methylation process silences pluripotency genes, which reduces differentiation potential, although other genes may undergo demethylation to become expressed [ 7 ]. It is important to emphasize that stem cell identity, together with its morphological characteristics, is also related to its epigenetic profile [ 8 , 9 ].
According to Brindley [ 10 ], there is a relationship between epigenetic changes, pluripotency, and cell expansion conditions, which emphasizes that unmethylated regions appear to be serum-dependent.
Spontaneous differentiation of hESCs causes the formation of a heterogeneous cell population. There is a different result, however, when commitment signals in forms of soluble factors and culture conditions are applied and enable the selection of progenitor cells.
EBs can be studied instead of embryos or animals to predict their effects on early human development. There are many different methods for acquiring EBs, such as bioreactor culture [ 13 ], hanging drop culture [ 12 ], or microwell technology [ 14 , 15 ].
These methods allow specific precursors to form in vitro [ 16 ]. The essential part of these culturing procedures is a separation of inner cell mass to culture future hESCs Fig. Rosowski et al. When the colony reaches the appropriate size, cells must be separated.
Because the classical utilization of hESCs caused ethical concerns about gastrulas used during procedures, Chung et al. Additionally, Zhang et al. Culturing of pluripotent stem cells in vitro. Three days after fertilization, totipotent cells are formed. Blastocysts with ICM are formed on the sixth day after fertilization. Pluripotent stem cells from ICM can then be successfully transmitted on a dish.
Cell passaging is used to form smaller clusters of cells on a new culture surface [ 21 ]. There are four important passaging procedures. Enzymatic dissociation is a cutting action of enzymes on proteins and adhesion domains that bind the colony.
It is a gentler method than the manual passage. It is crucial to not leave hESCs alone after passaging. Solitary cells are more sensitive and can easily undergo cell death; collagenase type IV is an example [ 22 , 23 ]. Manual passage , on the other hand, focuses on using cell scratchers.
The selection of certain cells is not necessary. This should be done in the early stages of cell line derivation [ 24 ]. Trypsin utilization allows a healthy, automated hESC passage.
Good Manufacturing Practice GMP -grade recombinant trypsin is widely available in this procedure [ 24 ]. However, there is a risk of decreasing the pluripotency and viability of stem cells [ 25 ]. Trypsin utilization can be halted with an inhibitor of the protein rho-associated protein kinase ROCK [ 26 ].
Ethylenediaminetetraacetic acid EDTA indirectly suppresses cell-to-cell connections by chelating divalent cations. Their suppression promotes cell dissociation [ 27 ]. Stem cells require a mixture of growth factors and nutrients to differentiate and develop. The medium should be changed each day.
Traditional culture methods used for hESCs are mouse embryonic fibroblasts MEFs as a feeder layer and bovine serum [ 28 ] as a medium. Martin et al. Feeder layers prevent uncontrolled proliferation with factors such as leukaemia inhibitory factor LIF [ 30 ].
First feeder layer-free culture can be supplemented with serum replacement, combined with laminin [ 31 ]. This causes stable karyotypes of stem cells and pluripotency lasting for over a year. Initial culturing media can be serum e. It is not yet fully known whether culture systems developed for hESCs can be allowed without adaptation in iPSC cultures.
The turning point in stem cell therapy appeared in , when scientists Shinya Yamanaka, together with Kazutoshi Takahashi, discovered that it is possible to reprogram multipotent adult stem cells to the pluripotent state.
This new form of stem cells was named iPSCs. One year later, the experiment also succeeded with human cells [ 36 ]. After this success, the method opened a new field in stem cell research with a generation of iPSC lines that can be customized and biocompatible with the patient.
Recently, studies have focused on reducing carcinogenesis and improving the conduction system. Retroviral-mediated transduction induces pluripotency in isolated patient somatic cells. Target cells lose their role as somatic cells and, once again, become pluripotent and can differentiate into any cell type of human body.
This caused a complete reversion of somatic cell development [ 37 ]. The results of his experiment became an immense discovery since it was previously believed that cell differentiation is a one-way street only, but his experiment suggested the opposite and demonstrated that it is even possible for a somatic cell to again acquire pluripotency [ 38 ]. The latter was a discovery made by Davis R. Three genes were found that originally appeared in myoblasts. The enforced expression of only one of the genes, named myogenic differentiation 1 Myod1 , caused the conversion of fibroblasts into myoblasts, showing that reprogramming cells is possible, and it can even be used to transform cells from one lineage to another [ 39 ].
Although pluripotency can occur naturally only in embryonic stem cells, it is possible to induce terminally differentiated cells to become pluripotent again.
The process of direct reprogramming converts differentiated somatic cells into iPSC lines that can form all cell types of an organism. Reprogramming focuses on the expression of oncogenes such as Myc and Klf4 Kruppel-like factor 4. This process is enhanced by a downregulation of genes promoting genome stability, such as p Additionally, cell reprogramming involves histone alteration.
All these processes can cause potential mutagenic risk and later lead to an increased number of mutations. Quinlan et al. Based on those studies, it was confirmed that although there were single mutations in the non-genetic region, there were non-retrotransposon insertions.
This led to the conclusion that current reprogramming methods can produce fully pluripotent iPSCs without severe genomic alterations. During the course of development from pluripotent hESCs to differentiated somatic cells, crucial changes appear in the epigenetic structure of these cells.
There is a restriction or permission of the transcription of genes relevant to each cell type. When somatic cells are being reprogrammed using transcription factors, all the epigenetic architecture has to be reconditioned to achieve iPSCs with pluripotency [ 41 ]. However, cells of each tissue undergo specific somatic genomic methylation. This influences transcription, which can further cause alterations in induced pluripotency [ 42 ]. Because pluripotent cells can propagate indefinitely and differentiate into any kind of cell, they can be an unlimited source, either for replacing lost or diseased tissues.
At first, fibroblasts were used as a source of iPSCs. Because a biopsy was needed to achieve these types of cells, the technique underwent further research. Researchers investigated whether more accessible cells could be used in the method.
Further, other cells were used in the process: peripheral blood cells, keratinocytes, and renal epithelial cells found in urine. In , pancreatic exocrine cells were shown to be reprogrammed to functional, insulin-producing beta cells [ 43 ]. The best stem cell source appears to be the fibroblasts, which is more tempting in the case of logistics since its stimulation can be fast and better controlled [ 44 ].
The self-renewal and differentiation capabilities of iPSCs have gained significant interest and attention in regenerative medicine sciences. To study their abilities, a quality-control assay is needed, of which one of the most important is the teratoma formation assay. Teratomas are benign tumours.
Teratomas are capable of rapid growth in vivo and are characteristic because of their ability to develop into tissues of all three germ layers simultaneously. This difference may be connected to different differentiation methods and cell origins. Most commonly, the teratoma assay involves an injection of examined iPSCs subcutaneously or under the testis or kidney capsule in mice, which are immune-deficient [ 47 ].
After injection, an immature but recognizable tissue can be observed, such as the kidney tubules, bone, cartilage, or neuroepithelium [ 30 ]. The injection site may have an impact on the efficiency of teratoma formation [ 48 ]. There are three groups of markers used in this assay to differentiate the cells of germ layers. For the mesoderm, derivatives can be used, e. As ectodermal markers, class III B botulin or keratin can be used for keratinocytes. Teratoma formation assays are considered the gold standard for demonstrating the pluripotency of human iPSCs, demonstrating their possibilities under physiological conditions.
Due to their actual tissue formation, they could be used for the characterization of many cell lineages [ 50 ]. To be useful in therapy, stem cells must be converted into desired cell types as necessary or else the whole regenerative medicine process will be pointless. Understanding and using signalling pathways for differentiation is an important method in successful regenerative medicine. In directed differentiation, it is likely to mimic signals that are received by cells when they undergo successive stages of development [ 51 ].
The extracellular microenvironment plays a significant role in controlling cell behaviour. By manipulating the culture conditions, it is possible to restrict specific differentiation pathways and generate cultures that are enriched in certain precursors in vitro. However, achieving a similar effect in vivo is challenging.
It is crucial to develop culture conditions that will allow the promotion of homogenous and enhanced differentiation of ESCs into functional and desired tissues. Regarding the self-renewal of embryonic stem cells, Hwang et al. This is because cell and tissue therapy requires the maintenance of large quantities of undifferentiated hESCs, which does not make feeder cells suitable for such tasks. Most directed differentiation protocols are formed to mimic the development of an inner cell mass during gastrulation.
During this process, pluripotent stem cells differentiate into ectodermal, mesodermal, or endodermal progenitors. Mall molecules or growth factors induce the conversion of stem cells into appropriate progenitor cells, which will later give rise to the desired cell type. Each candidate factor must be tested on various concentrations and additionally applied to various durations because the precise concentrations and times during which developing cells in embryos are influenced during differentiation are unknown.
Regarding endoderm formation, a higher activin A concentration may be required [ 58 , 59 ]. There are numerous protocols about the methods of forming progenitors of cells of each of germ layers, such as cardiomyocytes [ 60 ], hepatocytes [ 61 ], renal cells [ 62 ], lung cells [ 63 , 64 ], motor neurons [ 65 ], intestinal cells [ 66 ], or chondrocytes [ 67 ].
In addition, it could also provide the possibility to form exogenous hepatocytes for drug toxicity testing [ 68 ]. Levels of concentration and duration of action with a specific signalling molecule can cause a variety of factors.
Unfortunately, for now, a high cost of recombinant factors is likely to limit their use on a larger scale in medicine. The more promising technique focuses on the use of small molecules. These can be used for either activating or deactivating specific signalling pathways. They enhance reprogramming efficiency by creating cells that are compatible with the desired type of tissue. It is a cheaper and non-immunogenic method. One of the successful examples of small-molecule cell therapies is antagonists and agonists of the Hedgehog pathway.
They show to be very useful in motor neuron regeneration [ 69 ]. Endogenous small molecules with their function in embryonic development can also be used in in vitro methods to induce the differentiation of cells; for example, retinoic acid, which is responsible for patterning the nervous system in vivo [ 70 ], surprisingly induced retinal cell formation when the laboratory procedure involved hESCs [ 71 ].
The efficacy of differentiation factors depends on functional maturity, efficiency, and, finally, introducing produced cells to their in vivo equivalent. Topography, shear stress, and substrate rigidity are factors influencing the phenotype of future cells [ 72 ]. The control of biophysical and biochemical signals, the biophysical environment, and a proper guide of hESC differentiation are important factors in appropriately cultured stem cells.
In the past, protocols used for stem cell transplantation required animal-derived products [ 73 ]. The risk of introducing animal antigens or pathogens caused a restriction in their use. Due to such limitations, the technique required an obvious update [ 74 ].
Now, it is essential to use xeno-free equivalents when establishing cell lines that are derived from fresh embryos and cultured from human feeder cell lines [ 75 ]. In this method, it is crucial to replace any non-human materials with xeno-free equivalents [ 76 ]. There are many organizations and international initiatives, such as the National Stem Cell Bank, that provide stem cell lines for treatment or medical research [ 77 ]. Stem cells have great potential to become one of the most important aspects of medicine.
In addition to the fact that they play a large role in developing restorative medicine, their study reveals much information about the complex events that happen during human development.
In the former cell, DNA is arranged loosely with working genes. When signals enter the cell and the differentiation process begins, genes that are no longer needed are shut down, but genes required for the specialized function will remain active. This process can be reversed, and it is known that such pluripotency can be achieved by interaction in gene sequences.
Takahashi and Yamanaka [ 78 ] and Loh et al. Many serious medical conditions, such as birth defects or cancer, are caused by improper differentiation or cell division. Currently, several stem cell therapies are possible, among which are treatments for spinal cord injury, heart failure [ 80 ], retinal and macular degeneration [ 81 ], tendon ruptures, and diabetes type 1 [ 82 ].
Stem cell research can further help in better understanding stem cell physiology. This may result in finding new ways of treating currently incurable diseases.
These stem cells appear to provide an accurate paradigm model system to study tissue-specific stem cells, and they have potential in regenerative medicine. Multipotent haematopoietic stem cell HSC transplantation is currently the most popular stem cell therapy. Target cells are usually derived from the bone marrow, peripheral blood, or umbilical cord blood [ 83 ]. HSCs are responsible for the generation of all functional haematopoietic lineages in blood, including erythrocytes, leukocytes, and platelets.
HSC transplantation solves problems that are caused by inappropriate functioning of the haematopoietic system, which includes diseases such as leukaemia and anaemia. However, when conventional sources of HSC are taken into consideration, there are some important limitations. First, there is a limited number of transplantable cells, and an efficient way of gathering them has not yet been found. There is also a problem with finding a fitting antigen-matched donor for transplantation, and viral contamination or any immunoreactions also cause a reduction in efficiency in conventional HSC transplantations.
Haematopoietic transplantation should be reserved for patients with life-threatening diseases because it has a multifactorial character and can be a dangerous procedure. Stem cells can be used in new drug tests. Each experiment on living tissue can be performed safely on specific differentiated cells from pluripotent cells.
If any undesirable effect appears, drug formulas can be changed until they reach a sufficient level of effectiveness. The drug can enter the pharmacological market without harming any live testers. However, to test the drugs properly, the conditions must be equal when comparing the effects of two drugs.
To achieve this goal, researchers need to gain full control of the differentiation process to generate pure populations of differentiated cells. One of the biggest fears of professional sportsmen is getting an injury, which most often signifies the end of their professional career.
This applies especially to tendon injuries, which, due to current treatment options focusing either on conservative or surgical treatment, often do not provide acceptable outcomes. Problems with the tendons start with their regeneration capabilities. Instead of functionally regenerating after an injury, tendons merely heal by forming scar tissues that lack the functionality of healthy tissues.
Factors that may cause this failed healing response include hypervascularization, deposition of calcific materials, pain, or swelling [ 84 ]. Additionally, in addition to problems with tendons, there is a high probability of acquiring a pathological condition of joints called osteoarthritis OA [ 85 ]. OA is common due to the avascular nature of articular cartilage and its low regenerative capabilities [ 86 ].
Although arthroplasty is currently a common procedure in treating OA, it is not ideal for younger patients because they can outlive the implant and will require several surgical procedures in the future. These are situations where stem cell therapy can help by stopping the onset of OA [ 87 ]. However, these procedures are not well developed, and the long-term maintenance of hyaline cartilage requires further research.
Osteonecrosis of the femoral hip ONFH is a refractory disease associated with the collapse of the femoral head and risk of hip arthroplasty in younger populations [ 88 ]. Although total hip arthroplasty THA is clinically successful, it is not ideal for young patients, mostly due to the limited lifetime of the prosthesis.
An increasing number of clinical studies have evaluated the therapeutic effect of stem cells on ONFH. Most of the authors demonstrated positive outcomes, with reduced pain, improved function, or avoidance of THA [ 89 , 90 , 91 ].
Ageing is a reversible epigenetic process. The first cell rejuvenation study was published in [ 92 ]. Cells from aged individuals have different transcriptional signatures, high levels of oxidative stress, dysfunctional mitochondria, and shorter telomeres than in young cells [ 93 ].
There is a hypothesis that when human or mouse adult somatic cells are reprogrammed to iPSCs, their epigenetic age is virtually reset to zero [ 94 ]. In their study, Ocampo et al. Their procedure revealed that these genes can also be used for effective regenerative treatment [ 97 ]. The main challenge of their method was the need to employ an approach that does not use transgenic animals and does not require an indefinitely long application.
The first clinical approach would be preventive, focused on stopping or slowing the ageing rate. Later, progressive rejuvenation of old individuals can be attempted.
In the future, this method may raise some ethical issues, such as overpopulation, leading to lower availability of food and energy. For now, it is important to learn how to implement cell reprogramming technology in non-transgenic elder animals and humans to erase marks of ageing without removing the epigenetic marks of cell identity. Stem cells can be induced to become a specific cell type that is required to repair damaged or destroyed tissues Fig.
Currently, when the need for transplantable tissues and organs outweighs the possible supply, stem cells appear to be a perfect solution for the problem. The most common conditions that benefit from such therapy are macular degenerations [ 98 ], strokes [ 99 ], osteoarthritis [ 89 , 90 ], neurodegenerative diseases, and diabetes [ ]. Due to this technique, it can become possible to generate healthy heart muscle cells and later transplant them to patients with heart disease. Stem cell experiments on animals.
These experiments are one of the many procedures that proved stem cells to be a crucial factor in future regenerative medicine. In the case of type 1 diabetes, insulin-producing cells in the pancreas are destroyed due to an autoimmunological reaction. As an alternative to transplantation therapy, it can be possible to induce stem cells to differentiate into insulin-producing cells [ ].
They can be stored in a tissue bank to be an essential source of human tissue used for medical examination. The problem with conventional differentiated tissue cells held in the laboratory is that their propagation features diminish after time. This does not occur in iPSCs. The umbilical cord is known to be rich in mesenchymal stem cells. Due to its cryopreservation immediately after birth, its stem cells can be successfully stored and used in therapies to prevent the future life-threatening diseases of a given patient.
Stem cells of human exfoliated deciduous teeth SHED found in exfoliated deciduous teeth has the ability to develop into more types of body tissues than other stem cells [ ] Table 1. Techniques of their collection, isolation, and storage are simple and non-invasive. Among the advantages of banking, SHED cells are:. Guaranteed donor-match autologous transplant that causes no immune reaction and rejection of cells [ ]. Not subject to the same ethical concerns as embryonic stem cells [ ]. In contrast to cord blood stem cells, SHED cells are able to regenerate into solid tissues such as connective, neural, dental, or bone tissue [ , ].
In , two researchers, Katsuhiko Hayashi et al. They succeeded in delivering healthy and fertile pups in infertile mice. The experiment was also successful for female mice, where iPSCs formed fully functional eggs. Young adults at risk of losing their spermatogonial stem cells SSC , mostly cancer patients, are the main target group that can benefit from testicular tissue cryopreservation and autotransplantation.
Effective freezing methods for adult and pre-pubertal testicular tissue are available [ ]. Qiuwan et al. For now, reaching successful infertility treatments in humans appears to be only a matter of time, but there are several challenges to overcome. First, the process needs to have high efficiency; second, the chances of forming tumours instead of eggs or sperm must be maximally reduced.
The last barrier is how to mature human sperm and eggs in the lab without transplanting them to in vivo conditions, which could cause either a tumour risk or an invasive procedure. In neuroscience, the discovery of neural stem cells NSCs has nullified the previous idea that adult CNS were not capable of neurogenesis [ , ]. Neural stem cells are capable of improving cognitive function in preclinical rodent models of AD [ , , ]. Awe et al. PD is an ideal disease for iPSC-based cell therapy [ ].
Although the results were not uniform, they showed that therapies with pure stem cells are an important and achievable therapy. Teeth represent a very challenging material for regenerative medicine. They are difficult to recreate because of their function in aspects such as articulation, mastication, or aesthetics due to their complicated structure.
Currently, there is a chance for stem cells to become more widely used than synthetic materials. Teeth have a large advantage of being the most natural and non-invasive source of stem cells. For now, without the use of stem cells, the most common periodontological treatments are either growth factors, grafts, or surgery. For example, there are stem cells in periodontal ligament [ , ], which are capable of differentiating into osteoblasts or cementoblasts, and their functions were also assessed in neural cells [ ].
Tissue engineering is a successful method for treating periodontal diseases. Stem cells of the root apical areas are able to recreate periodontal ligament.
One of the possible methods of tissue engineering in periodontology is gene therapy performed using adenoviruses-containing growth factors [ ]. As a result of animal studies, dentin regeneration is an effective process that results in the formation of dentin bridges [ ].
Enamel is more difficult to regenerate than dentin. After the differentiation of ameloblastoma cells into the enamel, the former is destroyed, and reparation is impossible. Medical studies have succeeded in differentiating bone marrow stem cells into ameloblastoma [ ].
Healthy dental tissue has a high amount of regular stem cells, although this number is reduced when tissue is either traumatized or inflamed [ ]. There are several dental stem cell groups that can be isolated Fig. Localization of stem cells in dental tissues. Periodontal ligaments stem cells are located in the periodontal ligament.
Apical papilla consists of stem cells from the apical papilla SCAP. These were the first dental stem cells isolated from the human dental pulp, which were [ ] located inside dental pulp Table 2. They have osteogenic and chondrogenic potential. Mesenchymal stem cells MSCs of the dental pulp, when isolated, appear highly clonogenic; they can be isolated from adult tissue e. MSCs differentiate into odontoblast-like cells and osteoblasts to form dentin and bone.
Their best source locations are the third molars [ ]. DPSCs are the most useful dental source of tissue engineering due to their easy surgical accessibility, cryopreservation possibility, increased production of dentin tissues compared to non-dental stem cells, and their anti-inflammatory abilities. These cells have the potential to be a source for maxillofacial and orthopaedic reconstructions or reconstructions even beyond the oral cavity. DPSCs are able to generate all structures of the developed tooth [ ].
In particular, beneficial results in the use of DPSCs may be achieved when combined with other new therapies, such as periodontal tissue photobiomodulation laser stimulation , which is an efficient technique in the stimulation of proliferation and differentiation into distinct cell types [ ].
DPSCs can be induced to form neural cells to help treat neurological deficits. Stem cells of human exfoliated deciduous teeth SHED have a faster rate of proliferation than DPSCs and differentiate into an even greater number of cells, e. SHED do not undergo the same ethical concerns as embryonic stem cells. DPSCs alone were tested and successfully applied for alveolar bone and mandible reconstruction [ ]. These cells are used in periodontal ligament or cementum tissue regeneration.
PDLSCs exist both on the root and alveolar bone surfaces; however, on the latter, these cells have better differentiation abilities than on the former [ ].
PDLSCs have become the first treatment for periodontal regeneration therapy because of their safety and efficiency [ , ]. These cells are mesenchymal structures located within immature roots.
They are isolated from human immature permanent apical papilla. SCAP are the source of odontoblasts and cause apexogenesis. These stem cells can be induced in vitro to form odontoblast-like cells, neuron-like cells, or adipocytes.
These cells are loose connective tissues surrounding the developing tooth germ. DFCs contain cells that can differentiate into cementoblasts, osteoblasts, and periodontal ligament cells [ , ]. Additionally, these cells proliferate after even more than 30 passages [ ].
DFCs are most commonly extracted from the sac of a third molar. When DFCs are combined with a treated dentin matrix, they can form a root-like tissue with a pulp-dentin complex and eventually form tooth roots [ ]. Dental pulp stem cells can differentiate into odontoblasts.
There are few methods that enable the regeneration of the pulp. The first is an ex vivo method. Proper stem cells are grown on a scaffold before they are implanted into the root channel [ ]. The second is an in vivo method. This method focuses on injecting stem cells into disinfected root channels after the opening of the in vivo apex.
Additionally, the use of a scaffold is necessary to prevent the movement of cells towards other tissues. For now, only pulp-like structures have been created successfully.
Methods of placing stem cells into the root channel constitute are either soft scaffolding [ ] or the application of stem cells in apexogenesis or apexification. Immature teeth are the best source [ ]. Nerve and blood vessel network regeneration are extremely vital to keep pulp tissue healthy. The potential of dental stem cells is mainly regarding the regeneration of damaged dentin and pulp or the repair of any perforations; in the future, it appears to be even possible to generate the whole tooth.
Such an immense success would lead to the gradual replacement of implant treatments. Mandibulary and maxillary defects can be one of the most complicated dental problems for stem cells to address. In , it was reported that it is possible to grow teeth from stem cells obtained extra-orally, e.
Pluripotent stem cells derived from human urine were induced and generated tooth-like structures. The physical properties of the structures were similar to natural ones except for hardness [ ].
Nonetheless, it appears to be a very promising technique because it is non-invasive and relatively low-cost, and somatic cells can be used instead of embryonic cells. More importantly, stem cells derived from urine did not form any tumours, and the use of autologous cells reduces the chances of rejection [ ]. Over recent years, graphene and its derivatives have been increasingly used as scaffold materials to mediate stem cell growth and differentiation [ ].
Both graphene and graphene oxide GO represent high in-plane stiffness [ ]. Because graphene has carbon and aromatic network, it works either covalently or non-covalently with biomolecules; in addition to its superior mechanical properties, graphene offers versatile chemistry.
Graphene exhibits biocompatibility with cells and their proper adhesion. It also tested positively for enhancing the proliferation or differentiation of stem cells [ ].
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