Hox6 function is Necessary for Endocrine Pancreas Development in vivo and in vitro.

[摘要] Diabetes affects millions of Americans and is caused by a disruption in β-cell abundance or function. Beta cells are one of the five types of endocrine cells found in the pancreas. A promising potential cellular therapy for the treatment of diabetes is the differentiation of human embryonic stem cells to insulin-producing beta cells. The study of endocrine pancreas development has been critical for the design of in vitro protocols for the differentiation of insulin-producing cells. The mesoderm is critical for the differentiation of endocrine cells and despite significant advances in our understanding of endocrine cell development, the function of the pancreatic mesodermal niche in this process is poorly understood. Fully elucidating the role of the mesoderm in endocrine cell development can greatly contribute to the design of protocols for the successful generation of functional β-cells in vitro. We have discovered a novel role for mesodermally expressed Hox6 genes in endocrine pancreas development. Inactivation of all three Hox6 paralogs leads to a dramatic loss of endocrine cells, including beta cells, as well as mild delays and disruptions in branching and exocrine cell differentiation. Loss of Hox6 function in the mesenchyme of the pancreas results in reduced expression of Wnt5a in the pancreatic mesenchyme. This leads to subsequent loss of expression of Wnt inhibitors Sfrp3 and Dkk1 in endocrine progenitor cells.In addition to a critical role in endocrine pancreas differentiation in vivo, we have also shown that Hox6 function is critical for the differentiation of insulin-producing cells in vitro. Utilizing a differentiation protocol that directs endoderm to insulin-producing cells, we show that mesoderm with a Hox expression profile appropriate for the pancreatic region is also generated. Loss-of-function of Hox6 impairs the ability of mESCs to differentiate to insulin-producing cells in vitro, similar to what we observe in vivo. Further elucidation of the mechanisms involved in mesodermal support of pancreatic endoderm and insulin-producing cells will contribute to protocols to generate replacement beta cells for the treatment of diabetes.

[发布机构] University of Michigan

[效力级别] Molecular

[关键词] Hox6 function in pancreatic endocrine cell development;Molecular;Cellular and Developmental Biology;Science;Cellular and Molecular Biology