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Neurology India, Vol. 59, No. 4, July-August, 2011, pp. 555-557 Topic of the Issue: Review Article Induced pluripotent stem cells and promises of neuroregenerative medicine Ashok Verma1, Nipun Verma2 1 University of Miami Miller School of Medicine, Miami, Florida, USA PMID: 21891933 DOI: 10.4103/0028-3886.84337 Keywords: Cell therapy, embryonic stem cell, induced stem cell, multipotent, pluripotent Neurodegenerative disorders represent a growing public health challenge. According to World Health Organization (WHO) estimates, [1] later age neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease make over 15% of the global burden of neurological illnesses, and the incidence of these disorders is expected to rise as life expectancy rises worldwide. Currently available therapy for neurodegenerative diseases is limited to partial relief of certain symptoms and the use of existing therapies often results in disabling side-effects. None of the currently available therapies slows or arrests the progressive clinical course of these disorders. The development of safe and efficacious preventive and curative therapies is urgently needed to reverse the tide of the emerging epidemiology of neurodegenerative disorders. It is in this context that stem cell research in recent years has caught public attention for novel restorative and replacement therapies in neurodegenerative disorders. This brief review summarizes the progress that has been made in stem cell research over the last few years, with an emphasis on the emergence of new induced pluripotent stem cells (iPS), the advantages of iPS over other stem cell platforms, and the role of iPS in understanding the disease mechanisms and devising potential cell therapies. Current Stem Cell Platform Embryonic stem cells A human embryo at the preimplantation stage (blastocyst, about 200-cell stage) is comprised of inner cell mass (ICM) and trophoblast. Cells of ICM are pluripotent and give rise to the embryo proper while trophoblast gives rise to the extraembryonic tissue required during gestation. A fertilized ovum on the other hand is totipotent as it can result in subsequent blastocyst and the whole fetus following successful implantation. Embryonic stem cells (ES) are derived from ICM and these cells have the potential to give rise to all tissues of the adult body through sequential differentiation of the ectoderm, endoderm, and mesoderm germ layers. All currently existing human ES lines are derived from the discarded fertilized ovum during in vitro fertilization (IVF) procedures. ES cells have been reported to develop into a comprehensive array of cell types under appropriate circumstances. However, meaningful therapeutic use of human ES has not yet been realized, despite reports of promising results in animal studies of neurological diseases [2] and Type 1 diabetes. [3] Umbilical cord blood-derived stem cells Umbilical cord blood (UBC)-derived progenitor cells comprise a heterogeneous pool of cells and it includes hematopoietic stem cells and embryonic-like stem cells. [4] These cells can be categorized as multipotent rather than pluripotent, as they are capable of giving rise to only hematopoietic and a limited spectrum of non-hematopoietic lineage cells. These cells have not been reported to possess the ability to give rise to the whole spectrum of adult body cells. However, storage of UBC samples has become a common commercialized venture worldwide as a result of long-term biobanking facilities. Adult stem cells Adult stem cells are tissue-resident progenitor cells, such as bone marrow-derived mesenchymal stem cells (MSC) and progenitor neurons in the periventricular and hippocampal regions of the brain. These cells are also multipotent in expression and they have been used in both site-directed and systemic deliveries of cells in a variety of disease models. Easy availability and multipotency of bone marrow-derived MSC have made them a common tool in tissue engineering experiments. [5] Bioengineered stem cells Bioengineered stem cells are derived using in vitro techniques to achieve multi- or pluripotency in adult differentiated cells. The bioengineering techniques that have been used to create pluripotency in committed adult cells can be classified into two general categories: somatic cell nuclear transfer (SCNT) technique and transcription factor-derived nuclear reprogramming or induced pluripotent stem cells (iPS) technology. SCNT is cloning as was demonstrated in 1997 through the creation of Dolly the sheep. [6] As the name SCNT suggests, it is simply the transfer of a somatic nucleus into an enucleated oocyte. This paradigm gives rise to a cloned zygote from which ES can subsequently be harvested. In contrast to the SCNT strategy in which an oocytic environment is required, iPS are derived by a novel technique in which nuclear reprogramming of ordinary adult cells is done by using a cocktail of transcription factors. [7] First reported in 2006, the iPS technology has been found to be remarkably reproducible and some say ridiculously easy [8] requiring only four factors (Oct4, Sox2, c-Myc, and Klf4). [7] As evidenced from the emerging literature from non-human iPS experiments, these cells meet the most stringent of tests for pluripotency (similar to EC), even up to autonomous capacity for embryogenesis. [9] Thus, although multiple tools currently exist to generate human stem cells, only ES collected from discarded embryos during IVF procedures and iPS bioengineered from adult cells qualify for strict 'pluripotent' status. As the field of nuclear reprogramming technology is unfolding before us, early results indicate that iPS technology offers distinct biological and ethical advantages for its use in human diseases. First, reprogrammed somatic cells provide the opportunity for autologous cell transplant, thereby eliminating the need for immunosuppressive therapy. Second, tissue source (fibroblasts from skin biopsy, for example) for iPS is a whole lot easier and safer than IVF-derived embryo for ES. Third, iPS cells possess unlimited resource capacity from individual donors compared to the limited resource of ES from discarded IVF products. Finally, and most importantly, iPS technology avoids the often contentious ethical and political quandaries surrounding embryo destruction. As we look ahead, it may be reasonable to ask whether ES cells are necessary in the light of emerging iPS technology. Therapeutic Potential of Induced Pluripotent Stem Cells Aside from being an exciting research tool to probe embryogenesis and disease pathogenesis, iPS have potential for so-called 'disease modeling' for drug screening and custom-tailored cell therapy. Induced pluripotent stem cells and disease modeling for drug development The study of the disease mechanism in many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, is constrained by the limited accessibility of the affected tissue as well as the inability to grow the relevant cell types in cultures for extended periods of time. The principle behind 'disease modeling' is to derive iPS from the patient's own skin cells and then to differentiate them in vitro into the affected cell types, thereby recapitulating the disease process in a 'Petri dish'. One advantage of this paradigm is that the very cell type that is specifically compromised in disease can be recreated in culture and studied, even when the cell type is long lost in the patient. Further, iPS technology has the potential to provide an unlimited source for any desired specialized cells. Ultimately, the goal of this approach is to use these cell culture models of disease to screen and identify novel drugs to treat or prevent the disease. For example, iPS lines from patients suffering from spinal muscular atrophy [10] and familial dysautonomia [11] have been created that are providing novel data to understand the disease mechanisms. Remarkably, high-throughput preliminary screening for therapeutic small molecules has already begun in some neurodegenerative disorders. Induced pluripotent stem cells and cell therapy If autologous iPS are coaxed into the desired cell types, they can be transplanted as replacement tissue and it has obvious advantages over ES transplants. No immunosuppressive therapy is required following iPS transplantation because they are autologous in nature. Another key advantage of iPS is the possibility of repairing disease-causing mutations by homologous DNA recombination technology. Promising results in mice indeed suggest that the treatment of genetic disorders with iPS is feasible. [11] Despite some successes in animal models, iPS technology is not yet ready for human trials. The chief concern is safety; [12] current iPS protocols cannot efficiently eliminate residual and unwanted undifferentiated cells and just like EC, they tend to be oncogenic and form teratomas. Additionally, most patient-specific iPS have been generated using integrating vectors, which may not get silenced efficiently or could disrupt endogenous genes, and is a potential impediment in human iPS therapy. [13] Other hurdles include lack of efficient targeting strategies to repair mutant alleles. Recent observation that many mouse iPS harbor epigenetic abnormalities, they may develop genetic mutation on prolonged culture and they may continue to retain epigenetic memory of their donor cells also need to be addressed. [13],[14] Conclusions Created from adult cells by a simple genetic trick just five years ago, the iPS system seems to resemble the ES platform that might allow them to become any type of cell in the body. The iPS concept is so appealing that some scientists and policy-makers even argue that other approaches such as therapeutic cloning and ES research, which requires destruction of embryos, is unnecessary and should be halted. While many questions remain and more questions are bound to come up as iPS technology is applied in disease modeling and cell therapy programs, interesting insights have already been gained into the process of cell programming, such as the finding that cells undergo defined sequential molecular events that are influenced by the starting cell type as well as the choice and number of transcription factors. It remains to be tested, however, whether iPS reprogramming and differentiation works in the human system, and whether lineage converted cells are functionally equivalent to their in vivo counterparts. References
Copyright 2011 - Neurology India |
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