The Role of BMP4 in Endoderm and Pancreas Specification from Human Embryonic Stem Cells
Funding:
American Society of Transplant Surgeons
Principal Investigator:
Lab Website:
(Lab website not available at this time)
Project Summary:
A cure for type 1 diabetes will require replacing the insulin producing beta cells that are destroyed during disease progression. Considering that one of the major clinical obstacles is the limited supply of donor organs, a major goal of diabetes research is to generate a surplus of insulin-producing beta cells that could be used for transplantation.
One potential source of these cells is human embryonic stem cells (hESCs). hESCs are pluripotent cell lines with the potential to differentiate into many distinct mature cell types including insulin-producing cells. The long-term objective of this research is to generate purified populations of insulin-producing cells from hESCs that can be used in cell replacement therapy for type 1 diabetes.
We have demonstrated that under non-selective culture conditions, hESCs have the capacity to differentiate into pancreatic duodenal homeobox 1-positive (pdx1+) cells and cells expressing islet hormones, but the fraction of cells adopting these cell fates are low. With the goal of directing differentiation of hESCs to pancreatic fate, we considered known developmental signals and tissue interactions that are involved in formation of endoderm and/or commitment of endoderm to a pancreatic fate.
Studies in model organisms have shown that endodermal domains are patterned by interactions with overlying mesodermal tissue(s), which express several intercellular signaling molecules such as FGFs and bone morphogenetic proteins (BMPs). In particular, BMPs are known to participate in morphogenesis and cell fates in the developing embryo, including the pancreas. Based on an identified effector role of BMP4 signaling in murine pancreas development, we tested the hypothesis that BMP4 would promote the differentiation of hESCs into pancreas lineage cells. In preliminary studies, we found that BMP4 treatment of hESCs prior to EB formation results in the development of "endoderm competence" and a significant induction of endoderm- and pancreas-related genes at both the gene and protein level. Based on this finding we propose the following specific aims to study BMP4 induced pancreas specification in hESCs.
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First published: 07/15/02 Last updated: 10/12/08
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