MOJ ISSN: 2374-6912MOJCSR

Cell Science & Report
Review Article
Volume 2 Issue 5 - 2015
Therapeutic Potential of Totipotent, Pluripotent and Multipotent Stem Cells
Kiran Makhani1, Salima Mehboob Ali1, Sarah Yousuf1 and Shezaib Siddiqui2*
1Department of Biotechnology, University of Karachi, Pakistan
2International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Pakistan
Received: November 21, 2015 | Published: December 17, 2015
*Corresponding author: Shezaib Siddiqui, Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Pakistan, Tel: 92-335-3683716; Email:
Citation: Makhani K, Ali SM, Yousuf S, Siddiqui S (2015) Therapeutic Potential of Totipotent, Pluripotent and Multipotent Stem Cells. MOJ Cell Sci Rep 2(5): 00041. DOI: 10.15406/mojcsr.2015.02.00041

Abstract

The discovery of stem cells opened up a whole new arena of research for scientists. And the realizations of their therapeutic potential, promises sustainable cure for previously untreated diseases. Stem cells may broadly be classified into totipotent, pluripotent and multipotent and each of these classes show enormous therapeutic function. Totipotent stem cells can differentiate into 200 cell types of the body and also has the ability to reconstitute a stem cell-deprived organ, thereby opening ways to tissue regeneration and replacement therapies respectively. Similarly, Pluripotent stem cells have been made to differentiate into neural tissues, insulin secreting cells, cardiomyocytes, hematopoietic cells, osteoblasts, endothelial cells and hepatocytes successfully. Also, the prospects for reprogramming human somatic cells into induced Pluripotent Stem (iPS) cells have heralded a new era in the field of Stem Cell Therapeutics. In contrast, Multipotent stem cells also promises self-renewal as well as demonstrates plasticity to transdifferentiate into muscle, skeletal, liver, kidney, muscle, skin, neural, and cardiac cell lineages. Additionally, they are shown to serve as a gene delivery vehicle in vivo. This review spans around the therapeutic applications of these three major types of stem cells.

Keywords: Totipotent Stem Cells; Pluripotent Stem Cells; Multipotent Stem Cells; Induced Pluripotent Stem Cells; Transdifferentiation; Endothelial Progenitor Cells; Myeloid Lineage; Lymphoid Lineage

Abbreviations

MHC: Major Histocompatibility Complex; IPS: Induced Pluripotent Stem cells; MSCs: Mesenchymal Stem Cells; EPCs: Endothelial Progenitor Cells; BM: Bone Marrow; hTERT: human Telomerase Reverse Transcriptase

Introduction

The two fundamental characteristics of stem cells are the ability of unlimited self-regeneration and the production of at least one type of differentiated progeny cells [1]. Different kinds of stem cells have different potentials of differentiation. Totipotent stem cells are able to produce all types of cells. A zygote is a totipotent stem cell which can even produce cells that are not actually the part of the embryo, example placental cells. During embryonic development, cells gradually become confined to distinct paths of differentiation and hence become pluripotent that is they lose the capacity of forming extra embryonic tissue but retains the ability of differentiating into all types of adult cells [2]. As the development continues, cells, previously pluripotent become restricted hence now called as multipotent. Distinct characteristic of multipotent stem cells is they can only differentiate into cells of a particular lineage. For example hematopoietic stem cells possess the ability to produce all kinds of blood cells but not neurons or lung cells [3]. The continuous self-renewal and differentiating ability of stem cells has created modern research emphasis on it, especially in relation to its therapeutic use [2].

Therapeutic potential of totipotent stem cells
Totipotent stem cells: Totipotent stem cells, however, out of all the other types, presents an ideal approach to deal with the therapies related to the diseases [4]. Totipotency- a potential exhibited by the cell upon fusion of an egg with a sperm characterizes it among the most versatile class of cells [5]. The zygote that develops as a result of fusion of the gametes is a single totipotent cell which has the capability to divide into numerous identical cells; giving rise to any of the three germ layers of human (endoderm, ectoderm or mesoderm) as well as extra embryonic cells which include cytotrophoblast layer and a syncytiotrophoblast layer of the placenta [6]. In addition, the feature which makes these cells so distinctive from the others is the potential to proliferate and differentiate into a complete organism [4]. Unlike pluripotent cells which can specialize to form only the embryonic cells [7] and multipotent cells which can give rise to only two or more mature cell types [8], totipotent cells can replicate unlimitedly and differentiate into nearly all human cells such as of nerve and heart [5]. Correspondingly, the totipotent cells do not just have the potential to replicate into 16 identical cells within 4 days but they do so without even losing their Totipotency. When the zygote replicates to reach a 16-celled stage, it, however, starts to lose its Totipotency and transits to differentiate into a specialized cell [6].

Differentiating and regenerative potential: In accordance with studies and the experiments that have been conducted so far, the potency of the totipotent cells cannot be undermined by the fact that it can differentiate itself into about 200 cell types of a human body [6]. Several experiments have been carried out to observe this potential which includes the pioneering efforts made on rats as well as some on mammalian species by numerous scientists [9-12].

In 1992, results were documented that totipotent hematopoietic stem cells pretreated with 5-fluorouracil when injected into the mouse were observed to differentiate into myeloid and lymphoid progeny with a long term in vivo reconstituting ability even after 7 months of transplantation [13]. Similarly, another research conducted in the earlier years also reported the same result of differentiation of totipotent hematopoietic stem cells into myeloid and lymphoid lineages when seeded into the mouse with mild and severe endogenous defects [14]. Also, the research conducted using the totipotent cells and inducing them to differentiate into a variety of cells when cultured as embryonic bodies along with the adult neural stem cells in order to induce differentiation, has resulted in the generation of myocytes- the cells found in muscle tissue [15,16].

Therefore, successful differentiation and enormous therapeutic potentials of the totipotent cells has led scientists to envision the possible treatments of diseases through cell and gene therapy as well as tissue regeneration [5]. The replacement therapy whereby the totipotent stem cells are differentiated into the desired cells and subsequently transplanted into the damaged tissue has proved to be one of the ideal approaches in restoring the functions of the tissue [17]. Moreover, stem cell based treatments via regenerative strategy wherein the abnormal cells are replaced by the differentiated stem cells and tropic strategy which involves the secretion of several different mediators such as interleukins and neurotrophic factors has also enabled scientist to cure diseases, particularly retinal associated diseases [18].

Therapeutic potentials of pluripotent stem cells
Replacing the pluripotent stem cells: Several diseases are characterized by exhaustion of stem cells in body such as Fanconi Anemia (Genetic defects in hematopoietic stem cells) or failure of bone marrow due hematopoietic stem cells which results in leukemia and lymphoma. Other diseases like type 1 diabetes due to auto immune destruction of pancreatic beta cells and liver cirrhosis generate a condition in which cells of the affected organ cannot be replenished actively from stem cells of the body. Such diseases can be treated by replacing the stem cell pool or with direct organ transplantation. The lack of healthy and matched donors has made the method of using pluripotent stem cells more ideal [19]. Another report showed that the presence of hoxB4 gene stimulates the production of hematopoietic stem cells in mice, henceforth promising a therapy for humans with impaired hematopoiesis [20].

Differentiation and therapeutic application: In several trials, mouse pluripotent stem cells derived dopaminergic neurons have shown to repair motor dysfunction of Parkinson cases in rodent models [21,22]. Human pluripotent stem cells have also been differentiated into pancreatic cells producing insulin which can play a significant role for treating type I diabetes. Somatostatin and glucagon secreting pancreatic cells have also produced [23]. Aging and accidental injuries can cause irreversible destruction of cardiac tissues due to their rare mitosis characteristic which restricts the natural regeneration of myocardial cells. Successful attempts have been made to use pluripotent stem cells for cardiac grafting [24,25]. Trials for whole blood formation have also being done in mouse models [26]. However, obtaining stable blood derived from pluripotent embryonic stem cells was challenging [27]. Using human pluripotent stem cells neural tissues, insulin secreting cells, cardiomyocytes, hematopoietic cells, osteoblasts, endothelial cells and hepatocytes are being successfully produced [19].

Limitations
As inevitable, among all types of stem cells pluripotent stem cells have invaluable potential for therapeutic purposes but the problem of immune rejection of transplanted cells is a major hindrance in its wide spread clinical use. For example, embryonic pluripotent stem cells derived hematopoietic cells express a low level of class I MHC and hence become a target of natural killer cells. Along with this, the use of human embryos has become a major social and religious concern [28,29].

Induced pluripotent stem cells
In consideration to such problems, recently, trials for reprogramming human somatic cells into induced pluripotent stem cells are being performed using Oct4, Sox2, Klf4 and Myc transcription factors [30]. Induced pluripotent stem cells hold great promise for drug discovery, understanding disease mechanisms, cells and tissue replacement therapies and regenerative medicine [29].

Reprogramming of anemic mouse fibroblast cells and correction of gene by homologous recombination led to successful differentiation of the resulting iPS cells into hematopoietic progenitor cells which were subsequently transplanted back in to the mouse. Visible recovery was observed in the mouse after transplantation [30]. Dopamine neurons derived from iPS cells that were transplanted into adult rat brain suffering with Parkinson disease proved to provide substantial recovery from the diseased phenotype [31]. Ebert AD et al. [32] reports the generation of motor neurons using iPS cells derived from somatic cells of a patient diagnosed with spinal muscular atrophy [32]. Mice suffering with hemophilia A were protected in a death inducing bleeding assay after injection of iPS cells derived endothelial cells into the liver [33]. As the production of iPS cells involves the reprogramming of somatic cells therefore the use of iPS cells in the treatment of epigenetic related defects like myelodysplastic syndrome is valuable and possesses the potential to completely reverse the disease condition [34]. Robust advancements in iPS cells production have also led to the generation of clinically relevant cell lines free of genomic integration and oncogenes which will ultimately contributes to the development of several therapies for genetic and epigenetic defects [29].

Therapeutic potential of multipotent stem cells
Multipotent stem cells are cells that have the capacity to self-renew by dividing and to develop into multiple specialized cell types present in a specific tissue or organ [35].

Self-renewal: Mesenchymal stem cells (MSCs) found in many adult tissues are an attractive multipotent stem cell source [36]. During the last two decades, mesenchymal stem cells (MSCs) have emerged as a potential player for cell-based therapeutics. They have demonstrated efficacy in multiple types of cellular therapeutic strategies, including applications in treating children with osteogenesis imperfect, hematopoietic recovery, and bone tissue regeneration strategies [37-39]. Moreover, the ability of MSCs to differentiate into a variety of connective tissue cell types has rendered them useful in the augmentation, local repair and regeneration of bone, cartilage and tendon [40-43]. MSCs are also located in the wall of large and small blood vessels in, but not limited to, brain, spleen, liver, kidney, lung, muscle, thymus, and pancreas [44,45]. Therefore, they may serve as a cell source for therapies of diverse disorders such as diabetes, osteoporosis, arthritis, muscular degenerative disorders, and the regeneration blood vessel walls after tissue injuries [46-49].

Human studies have reported autologous whole bone marrow to improve posterior spinal fusion in adolescent idiopathic scoliosis when administered along with demineralize bone matrix [50]. Similar human trials have reported the efficacy of using autologous bone marrow aspirates combined with mineralized collagen matrix grafts for fusion of thoracolumbar fractures [51].

In addition to the MSCs, Hematopoietic Stem Cells may be used in autologous or allogeneic transplantations for the treatment of patients with diverse hematopoietic disorders and several inherited immune-deficient and autoimmune diseases and to reconstitute the hematopoietic cell lineages and immune system defense [52,53].

The in vivo induction of mobilization of BM-derived Endothelial Progenitor Cells (EPCs) into peripheral circulation or their activation can open prospects to promote neo-angiogenesis and vascular repair of injured areas [45,53-57]. As evidence, it has been observed that the injection of isolated human CD34-/CD133+/VEGFR2+/ CD14-EPC sub-population in nude mice with an injury in carotid artery led to their differentiation into endothelial cells and their subsequent incorporation into the endothelial layer of carotid artery lesion, resulting in a decrease in lesion size [55].

NSCs, genetically modified NSCs, or their further differentiated progeny could be used as therapeutic agents, owing to their intrinsic capacity to restore dysfunctional neurons in the brain by releasing neuro-regenerative molecules [58]. They are proposed to treat a variety of central nervous system disorders and several progressive and neurodegenerative diseases, characterized by deterioration and/or loss of neuronal cells, like, multiple sclerosis, Parkinson’s, Alzheimer’s, Amyotrophic Lateral Sclerosis, and Huntington’s diseases [53,59-64]. Moreover, this restoration of lost neuronal cells could also improve impairment in memory loss, abnormal control of movement, sensation, and other autonomic nervous functions.

Trans-differentiation: Recent advancements suggest that adult multipotent stem cells, previously thought to undergo tissue-specific differentiation, are potent of trans-differentiation as well. Trans-differentiation refers to differentiation of a cell into lineages other than its tissue of origin. For instance, bone marrow (BM) cells are observed to possess the ability to repopulate many non-hematopoietic tissues, such as neuro-ectodermal cells, skeletal myoblasts, cardiomyocytes, endothelium, hepatocytes and lung, gut, and skin epithelia [65-72]. Whereas, BM-derived circulating Hematopoietic Stem Cells and Endothelial Progenitor Cells within peripheral circulation are able to Trans-differentiate into cells of damaged non-hematopoietic tissues [73]. Also, BM-derived stem cells, such as endothelial progenitor cells, angioblasts, or CD34+ cells, when transplanted into ischemic myocardium incorporate into the sites of neovascularization and have shown to improve cardiac function [74-76]. Another evidence of trans-differentiation of multipotent stem cells reside in the ability of Mesenchymal Stem Cells to not only regenerate tissues of mesenchymal lineages, but also differentiate into cells derived from other embryonic layers, including neurons and epithelia in skin, lung, liver, intestine, kidney, and spleen [77-79].

Application in Gene transfer: Apart from their ability to self-renew and transdifferentiate, Multipotent Stem Cells have been used as vehicle to introduce exogenous DNA, making them important for tissue regeneration therapies. For example, MSCs infected with an adenovirus vector carrying dominant-negative mutant collagen type I gene have shown to repair the bone in individuals with osteogenesis imperfect, a brittle bone disease [80].

Prospects: Despite of such vast therapeutic potential of multipotent stem cells, adult MSCs lack telomerase activity [81]. Therefore, they show definite ex vivo proliferation capability, reach senescence and lose multi-lineage differentiation ability after 34-50 population doublings in culture. Thus, in order to utilize them to the maximum, it is required to develop methods to prolong the replicative capacity of MSCs with least unfavorable effects on their multi-potency. In this regard, several studies have shown forced ectopic expression of human telomerase reverse transcriptase (hTERT) in postnatal MSCs to extend their life span to more than 260 population doublings, without any impairment in their osteogenic, chondrogenic, adipogenic, neurogenic, and stromal differentiation potential [82-83].

Discussion

Intense research on stem cells during the last decades has provided vital information on the processes that govern tissue and organ formation, maintenance, regeneration, and repair after injuries [53,54,59,84-87]. Moreover, these advancements have offered great promise for developing novel successful stem cell-based medical treatments [73]. This is based on the possibility of stimulating their ex vivo and in vivo expansion and differentiation into functional progeny that could regenerate the injured tissues/organs in humans [53]. The field of stem-cell biology has further been catapulted forward by the startling development of reprogramming technology which has created powerful new opportunities for modeling human diseases and offers hope for personalized regenerative cell therapies [88].

Despite of immense development in the field of stem cell biology, further studies appear to be necessary for clinical therapeutic applications in humans. This includes investigation to optimize the experimental conditions for isolation, expansion, and differentiation of human stem/progenitor cells in vitro, ex vivo, and in vivo. Also, the identification of specific biomarkers to each type of adult stem/progenitor cells is a precursor for the characterization of their specific physiological functions. In addition, the loss functions of adult stem/ progenitor cells with aging and in specific pathological disorders need to be understood by the elucidation of the complex network of environmental signals that govern the self-renewal and differentiating capacities of these cells. This, in turn, can provide information on the sequence of molecular events that may be associated with each stage of development of a particular disease in humans, hence allowing for personalized therapy designing. In addition, the establishment of engraftment mechanisms of transplanted stem/progenitor cells in contrast to their nonfunctional or malignant counter-part could also lead to new, less toxic therapeutic transplant strategies [73].

Other obstacles in the way of this type of theory are mostly due to tissue transport, pharmacokinetics, and protein stability, which emphasizes the need to identify all the components of the secretome from which stem cells are extracted for the therapy and to develop novel release and delivery methods [89]. With the immense flow of research being carried out in the field of stem cell biology, these above mentioned issues will soon be encountered with success, paving way to life-saving therapies.

Conclusion

Extensive studies and numerous experiments carried out by the scientists have made substantial amount of information available over the years and has unfolded a new chapter of the promising use of stem cells as a therapeutic agent. With the ability to differentiate and proliferate into a spectrum of cells and therefore hold a prominent position in the field of regenerative as well as personalized medicine. Correspondingly, disorders associated with liver, retina, cardiovascular system or neurodegeneration which were previously untreatable due to the limitations exhibited by the immune system and also with respect to tissue regeneration have now been cured successfully and effectively [90]. Furthermore, in accordance with the results of Allison D. Ebert & Clive N. Svendsen published in Nature, stem cells provide a foothold platform for the process of drug screening as well as drug development; thereby, enabling scientists to study the effects of a drug directly on a human cell line rather than on animal models [1,91,92]. Consequently, with the aim to repair and replace the damaged organ or tissues, stem cells promise a vivid future and an unparallel approach for the treatment of nearly all pervasive and debilitating human diseases.

Acknowledgement

Many thanks to all teachers, trainers and friends for imparting enough suggestions and knowledge, which came out as this written review.

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