Stem Cell and Its Application to Therapeutics - Research Paper Example

?The Benefits of Stem Cell Research The much talked about and sought after controversial stem cell research and its application to therapeutics has gained momentum in the past few decades. This breakthrough in science is based on the simple principle of cellular regeneration. Stem cell therapy is an intervention technique in which a specialized set of cells is introduced into a damaged tissue or organ. The ability of these cells to auto-renew and differentiate substantially into any tissue of the body is of prime importance in treating various types of cancers or diseased organs. Since stem cells are mostly embryonic in nature and are treated as a xenograft, the rate of an implant rejection by the body is not very rare. A high rate of differentiation of stem cells and their easy integration with the surrounding cell matrix has made this therapy very popular. Various clinical trials are in progress, ranging from the management of cancers- particularly in bone marrow regeneration, diabetes, neurology and cardiovascular complications, to name a few. Stem cell therapy was, and still is of promising importance in the chemotherapy of certain cancers. It is a well known fact that chemotherapeutic agents, being non selective in nature, destroy both, the tumorigenic as well as the healthy, viable cells. An immediate replenishment of these cells is required in order to maintain optimal bodily functions, and this could be brought about by stem cell intervention, wherein the cells are derived from the embryonic placenta. This is the underlying principle of a bone marrow transplant. The marrow from a healthy donor supplies the viable hematopoietic stem cells to an immunocompromised individual who has low levels of these cells, due to either radiation or chemotherapy (Gonez and Knight). In this paper, I would like to discuss how stem cell research and transplantation techniques could be extended to patients diagnosed with Type I diabetes, the benefits and advantages versus the drawbacks, and the ethical issues one has to address while resorting to stem cell therapy. Type-1 Diabetes: Type-1, Insulin dependent diabetes mellitus (IDDM) or juvenile diabetes is an autoimmune disorder, in which the ?-cells of the islets of the Langerhans in the pancreas get affected or destroyed. As a result, the levels of insulin secreted are extremely low. Since this hormone plays the most important role in the uptake of the monosaccharide glucose by the cells, its depletion or absence results in high levels of circulating blood glucose. This condition is called hyperglycemia, and if blood glucose levels are unregulated for a prolonged period of time, could result in fatalities. Since this is an autoimmune disorder in which the cells damaged completely, the only possible therapy in management of this condition is by delivering insulin through external sources, via injections or pumps. Drugs, which act on the ? cells of the pancreas in Type 2 diabetes, will be ineffective in type 1 diabetics, due to the lack of functional cells. A pancreatic transplant is one of the methods of addressing this issue, however, a minimum of 4 donor pancreas from brain dead volunteers are required in order for the process to have some success (Zhao et al.). Since the likelihood and feasibility entails many variables, it is not one of the sought after processes aimed at therapy. Current research could thus be aimed at restoring functionality of the damaged pancreatic tissue by means of a stem cell intervention, which could gradually regenerate these cells to self-produce this hormone. Experimental studies demonstrate that xenografts, tissue stem cells and embryonic stem cells are considered as hot targets in aiming to treat this condition. Pancreatic cells have a complex stimulus-response mechanism, depending on a multitude of factors such as activation of ion channels, sensitization of peroxisome proliferator activated receptors, etc. Essentially, the 2 aspects that have to be taken into consideration are their capacity to synthesize and house insulin, and the ability to release it accordingly in order to maintain a steady blood glucose level of 80-105 mg/ dL, which indicates normoglycemia (Zhao, Jiang and Guo). Some potential sources of regenerative cells in the therapy of Type-1 diabetes are from insulin secreting cell lines from healthy volunteers, embryonic stem cells or tissue stem cells from either the pancreas, bone marrow or liver. The transformed cells obtained from human ? cells used in transplantation show unregulated multiplication and eventually lead to insulinomas (Soggia et al.). Islet Xenografts: Using the pancreatic islets of Langerhans from non-human sources such as bovine or porcine variants is one way of addressing replacement. Porcine insulin has been traditionally used in the management of diabetes and the procedure involved in obtaining the pancreas, after slaughtering the animal is well researched. This process of isolation of the porcine islets is similar to that of human islet preparation and purification. An added advantage is that the porcine genotype is readily amenable to genetic modification, which makes it easy to genetically re-engineer the insulin to human requirement. Successful transplantations have been carried out, but there have been adverse reactions associated with xenografts. The primary problem is the hyperimmune response to the foreign xenografts, which has been tackled by encapsulating the islets prior to transplantation. However, this method didn’t prove very beneficial, as there was a compromise in the functional aspect of insulin secretion (Ting et al.). The second drawback that surfaced was the manifestation of porcine endogenous retroviral sequences (PERV), which was activated and expressed following a transplant, which could serve as a potentially harmful novel form of viral infections in humans (Limbert et al.). Generation of ??cells from stem cells: Tissue stem cells were believed to generate only into the specific cells, tissue or organ they were genetically programmed to. Recent research has shown that varied tissue may have traits of progenitor cells capable of differentiating into insulin producing cells. Pancreatic stem cells do not have the capacity to multiply in vitro. However, experimental studies on mice have shown that when there is a damage or trauma to the pancreas, there is an upregulation in the pancreatic progenitor cells, which then start to differentiate into ? cells (Shufaro and Reubinoff). Neural stem cells and cells derived from the bone marrow function in a slightly different manner. These hematopoietic and glial cells are very versatile in development and differentiation, as they adapt themselves and produce insulin-secreting phenotypes, thus reversing the diabetic condition to some extent. In vivo treatment using the tissue engineering method: Islet transplant using the Edmonton protocol is in wide use in Australia. In this method, the pancreatic islets are carefully isolated from fresh cadavers, and are introduced into the hepatic portal vein of a Type 1 diabetic individual (Limbert et al.). These islet cells course through the blood stream, enter the spaces and sinusoids and attach themselves to the basement membrane of the liver. Without eliciting an antigenic response, they start behaving as functional ? cells and secrete insulin depending on the blood glucose levels (Zhao, Jiang and Guo). The disadvantage of this method, similar to that of a total pancreatic replacement, is the need of lifelong immunosuppressant drugs (Gonez and Knight). Cord blood stem cells Cord blood is unique in the fact that it circulates solely within the umbilical cord, which connects the embryo to the placenta (Zhao and Mazzone). During the stages at which the fetus is developing, nutrients from the mother to the fetus are transported via the umbilical blood. Post delivery, the umbilical blood and stem cells could be collected, cultured and used at a later stage (Zhao, Jiang and Guo). These cells have very low immunogenicity and are an excellent source for the generation of further stem cells. In addition to their convenient availability, they also adequately address the ethical issues associated with stem cell research. Cell reprogramming technique: This novel technique is employed to generate pluripotent stem cells from the existing pancreatic ? cells of the patients affected with type-1 diabetes. In order to achieve this, a special type of cells called fibroblasts are cultured and are subjected to specific retroviruses which encode the transcription factors responsible for conferring pluripotency on them(Zhao et al.). After this process, the cells begin to differentiate under controlled specialized conditions, into insulin secreting cells, which respond to the insulin signaling pathways. The intermediary steps leading to the final ? like cells are the endoderm phase and the pancreatic progenitor phase, which has been discussed earlier. This procedure offers researchers the benefit of limiting autoimmune responses of antigenicity, which are associated with transplants. However, this method, like the xenografts, has the potential to cause insulinomas and tumors (Soggia et al.). Ongoing studies are directed towards inducing the requisite genomic deletions and amplifications in order to achieve stability and better insulin secretory potential (Limbert et al.; Gonez and Knight). Immunosuppression: After a transplant, there always exists the possibility of immunogenicity. This occurs due to the expression of proteins such as Class I Major Histocompatibility Complex (MHC), in response to antigens such as macrophages, lymphocytes and dendritic cells. Although grafts and transplants are carried out after determining biochemical compatibility, there are other unexplained factors too, which may lead to a rejection. Thus, immunosuppressant drugs come into play, where the body’s innate ability to produce macrophages and T-cells which are responsible for protecting the immune function are suppressed (Ting et al.). This is one of the solutions undertaken to complete and maintain a successful stem cell transplant. However, this is a life long therapy, which will lead to a rejection of the transplant as soon as the immunosuppressant drugs are withdrawn (Soggia et al.). Controversies surrounding Stem cell research: Various religious and political views surround the use of stem cells for research. Many follow the train of thought that it is unethical to use embryonic stem cells, as procurement of these involves destruction of the embryo. The standard procedure involves culturing the cells from the embryo or umbilical cord blood cells, and generating cell lines. Religious and fanatic beliefs involve the principle that the sanctity of life is of utmost importance, which has come into existence due to the union of the sperm with an ovum, and it is morally unethical and improper to sacrifice this embryo, which has the potential to develop and generate into a human form. Others argue that there is a commencement in a trend in which women sell their embryos in order to make money, thus promoting abortions (Docherty, Bernardo and Vallier). Refuting the arguments: The classic explanations given to the above arguments involving justifying how an embryo is incapable of surviving outside the womb, and hence using an embryo for research does not tantamount to ‘killing or murder’. More than 33% of zygotes do not implant in the fallopian tubes after fertilization, which results in a loss of a larger number of embryos, which could have been put to better use by generating cell lines for research purposes. A certain cellular stage is attained after fertilization and is called the blastocyst differentiation, which is a mass of undifferentiated cells. These cells could be used for research without violating any religious or ethical beliefs. In vitro fertilization is a breakthrough in biotechnology and a widely accepted method of conception, with a relatively low success rate. In order to compensate for the feeble chances of success, and to increase the probability of successful fertilization and implantation of the zygote, test tube fertilization is implemented and a large number of unused embryos and zygotes are created (Shufaro and Reubinoff). Rather than letting these be disposed off, they could be better utilized in productive stem cell research. Other potential applications of stem cell research: The capacity of the central nervous system to regenerate certain specialized types of cells such as the myelin sheath, neural cells, glomeruli, etc. are very limited. Once neurodegenerative disorders such as multiple sclerosis or Parkinsonism set in, although pharmacotherapies exist in their management, a complete restoration of the damaged neurons is never achieved. Embryonic stem cell therapy is of great importance in management of cancers. Radiation and chemotherapy destroys viable cells, which results in a loss of function. Generation of astrocytes, glial cells, or neuronal cells to replace the affected cells has offered significant benefits. Transplantation of fetal dopaminergic neuronal cells significantly reduces the tremors and demyelination associated in patients suffering from Parkinsonism (Jones et al.). Damages caused to the myocardium on account of ischemia, strokes or infarcts is an age and diet related complication. Immediately after an attack, the functional myocardium is replaced by fibrotic tissue, which results in a loss of the cardiomyocytes. Fetal cardiomyocytes have the capacity to regenerate and repair the damaged cells, although they are very difficult to culture and procure (Holland and Stanley). Current research is centered on development of non-animal component based human embryonic stem cell, and in further development of progenitor cells differentiation and utilization, after decreasing immunogenicity (Gorba and Allsopp). The long-term effects following stem cell transplantation are under constant evaluation. Conclusions: Stem cell research has been one of the most successful and rewarding studies, which even today keeps opening up a Pandora’s box of unlimited possibilities. Although significant work has been carried out, the molecular mechanisms underlying the differentiation of these stem cells in vivo, the signaling pathways, and the effect of biochemical cascades on these novel cell lines is not completely understood. Like most chronic conditions, the proper management of Type 1 diabetes is of utmost importance in order for the person to sustain and maintain the permissible blood glucose levels. Stem cell transplant utilizing embryonic cells could be a boon to patients afflicted with this syndrome. Although light is visible at the end of the tunnel, it will take us a while to completely unravel and understand the fate of the transplanted tissue in humans. References: Docherty, K., A. S. Bernardo, and L. Vallier. "Embryonic Stem Cell Therapy for Diabetes Mellitus." Semin Cell Dev Biol 18.6 (2007): 827-38. Print. Gonez, L. J., and K. R. Knight. "Cell Therapy for Diabetes: Stem Cells, Progenitors or Beta-Cell Replication?" Mol Cell Endocrinol 323.1 (2010): 55-61. Print. Gorba, T., and T. E. Allsopp. "Pharmacological Potential of Embryonic Stem Cells." Pharmacol Res 47.4 (2003): 269-78. Print. Holland, A. M., and E. G. Stanley. "Stems Cells and the Price of Immortality." Stem Cell Res 2.1 (2009): 26-8. Print. Jones, P. M., et al. "Cell-Based Treatments for Diabetes." Drug Discov Today 13.19-20 (2008): 888-93. Print. Limbert, C., et al. "Beta-Cell Replacement and Regeneration: Strategies of Cell-Based Therapy for Type 1 Diabetes Mellitus." Diabetes Res Clin Pract 79.3 (2008): 389-99. Print. Shufaro, Y., and B. E. Reubinoff. "Therapeutic Applications of Embryonic Stem Cells." Best Pract Res Clin Obstet Gynaecol 18.6 (2004): 909-27. Print. Soggia, A., et al. "Cell-Based Therapy of Diabetes: What Are the New Sources of Beta Cells?" Diabetes Metab 37.5 (2011): 371-5. Print. Ting, A. E., et al. "Therapeutic Pathways of Adult Stem Cell Repair." Crit Rev Oncol Hematol 65.1 (2008): 81-93. Print. Zhao, Y., Z. Jiang, and C. Guo. "New Hope for Type 2 Diabetics: Targeting Insulin Resistance through the Immune Modulation of Stem Cells." Autoimmun Rev 11.2 (2011): 137-42. Print. Zhao, Y., et al. "New Type of Human Blood Stem Cell: A Double-Edged Sword for the Treatment of Type 1 Diabetes." Transl Res 155.5 (2010): 211-6. Print. Zhao, Y., and T. Mazzone. "Human Cord Blood Stem Cells and the Journey to a Cure for Type 1 Diabetes." Autoimmun Rev 10.2 (2010): 103-7. Print. Read More