Directed Differentiation of Human ESCs to Endoderm and Pancreatic Lineages
Funding:
Juvenile Diabetes Research Foundation International
Principal Investigator:
Lab Website:
(Lab website not available at this time)
Project Summary:
Objective: We have recently developed a novel culture protocol for differentiating human ES cells into endoderm and pancreatic precursor cells expressing PDX1 or Ipf1, a key regulatory gene necessary for pancreas development. The aims of the present study are to understand the mechanism through which this differentiation is occurring, and the signals involved, as a window onto human endoderm à pancreatic development, and to use this platform to generate a purified population of tumor-free, insulin-secreting beta-like cells.
Background/Rationale: Type I diabetes is a disease that would be amenable to stem cell-based therapy as it is characterized by the loss of a specific cell type, the beta cell. The success of clinical islet transplantation provides proof-of-principle that a cellular transplant can be effective, yet organ donor shortages stimulate the need for new sources of cells. Because of their ability to be expanded indefinitely and become many different cell types of the body, embryonic stem cells (ESCs) may one day provide the platform for a stem cell-based therapy for diabetes. Many studies have shown that murine and human ESCs are capable of differentiating into islet hormone producing cells, but protocols leading to enriched populations of pancreatic or islet precursor cells from human ESCs have not been developed. In addition, current differentiation protocols include the use of undefined media supplements and animal-derived factors that could ultimately pose a threat to human health following transplantation.
Description of Project: First, we intend to study the specific roles and interplay of two growth factors, bone morphogenetic protein 4 and basic fibroblast growth factor, in the development of endoderm and the early fate choices of human ESCs in culture. Secondly, we intend through serial refinements in media components and selection methods using magnetic bead sorting to improve the differentiation protocol and produce enriched populations of pancreatic precursor cells. These cell populations will ultimately be tested for how well they reverse diabetes in animals.
Anticipated Outcome: We anticipate this study will deepen our understanding of the signals and genes involved in endoderm germ layer formation in humans. These studies will refine the necessary components of this newly developed culture protocol and establish a method that is safe and free of animal products. It is ultimately hoped that through such studies insulin-expressing cells that function as mature beta cells can be derived in larger numbers from human ESCs.
Relevance to Type I Diabetes: Because our platform is human ESCs, our experiments will provide a window onto human endoderm and pancreatic development, which is currently not well-studied due to ethical considerations. A better understanding of how the endoderm and pancreas normally forms in humans will be critical to guiding HESCs towards insulin-secreting beta cells in a more uniform manner in future experiments. Ultimately, through modification of our novel protocol, we expect to develop a population of cells that can be used for transplantation into Type I diabetic patients.
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First published: 07/15/02 Last updated: 10/07/08
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