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Stem cell-based regenerative pharmacology for the treatment of diabetes mellitus

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abstract
Stem cell-based regenerative pharmacology is aimed at establishing stem and progenitor cells as effective treatment for preventing disease and facilitating organ replacement or repair. Diabetes mellitus (DM) is a group of chronic metabolic disorders characterized by high blood glucose levels. Type 1 DM (T1DM) is a lack of insulin production caused by autoimmune destruction of the beta-cells, while Type 2 DM (T2DM) is insulin resistance in peripheral tissue that leads to beta-cell exhaustion. Chronic hyperglycemia leads to serious long term complications. Transplantation of whole pancreas or isolated islets are promising approaches to restore insulin production in these patients; however, the severe shortage of organ donors and risk of allogeneic graft rejection have limited this treatment. Stem cells are an attractive starting source for producing pancreatic lineage derivatives to be used in treatment of DM as a form of cell replacement therapy, immunotherapy and in attempts to model diabetic disease phenotypes in vitro for identification of novel drug targets. Amniotic fluid stem (AFS) cells are a long-lived, bankable cell source possessing extensive differentiation capacity. We found that by genetic manipulation and culture condition modifications, AFS cells can be induced to produce insulin, making them a potential source of renewable insulin-producing cells for cell-replacement therapy in DM patients. We also discovered that AFS cells possess immunomodulatory properties and are able to inhibit lymphocyte activation by release of soluble factors in vitro. This quality makes AFS cells an ideal candidate for cell-based immunomodulation in early stages of T1DM to prevent the autoimmune response or in combination with allogeneic islet transplantation to prevent rejection. Finally, we developed pluripotent stem cells, embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, containing a deficiency in HNF4A expression that is known to cause a form of monogenic T2DM, maturity onset diabetes of the young 1 (MODY1). Pluripotent stem cells deficient in HNF4A, a gene which has a known role in beta-cell development and function, were used to model pancreatic development in vitro as a means to study the progression of disease pathology. We identified several genes potentially regulated by HNF4A in the gut tube endoderm stage of pancreatic lineage differentiation which may lead to identification of novel drug targets to treat DM.
subject
amniotic fluid
induced pluripotent
pancreas
stem cell
contributor
Moorefield, Emily (author)
Bishop, Colin (committee chair)
Soker, Shay (committee member)
Antinozzi, Peter (committee member)
Bowden, Donald (committee member)
Farney, Alan (committee member)
date
2012-06-12T08:36:01Z (accessioned)
2012-06-12T08:36:01Z (available)
2012 (issued)
degree
Molecular Medicine and Translational Science (discipline)
identifier
http://hdl.handle.net/10339/37293 (uri)
language
en (iso)
publisher
Wake Forest University
title
Stem cell-based regenerative pharmacology for the treatment of diabetes mellitus
type
Dissertation

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