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Hox6 genes modulate in vitro differentiation of mESCs to insulin-producing cells

Abstract

The differentiation of glucose-responsive, insulin-producing cells from ESCs in vitro is promising as a cellular therapy for the treatment of diabetes, a devastating and common disease. Pancreatic β-cells are derived from the endoderm in vivo and therefore most current protocols attempt to generate a pure population of first endoderm, then pancreas epithelium, and finally insulin-producing cells. Despite this, differentiation protocols result in mixed populations of cells that are often poorly defined, but also contain mesoderm. Using an in vitro mESC-to-β cell differentiation protocol, we show that expression of region-specific Hox genes is induced. We also show that the loss of function of the Hox6 paralogous group, genes expressed only in the mesenchyme of the pancreas (not epithelium), affect the differentiation of insulin-producing cells in vitro. This work is consistent with the important role for these mesoderm-specific factors in vivo and highlights contribution of supporting mesenchymal cells in in vitro differentiation.

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Acknowledgments

We would like to thank Dr. Thom Saunders, Elizabeth Hughes, and the University of Michigan Transgenic Animal Model Core for help deriving the mESC lines. The NIH Cellular and Molecular Biology Training Grant T32-GM007315 and the Training Program in Organogenesis T32-HD007505 supported BML. The project described was supported by Grant Number P30DK020572 (MDRC) from the National Institute of Diabetes and Digestive and Kidney Diseases, The American Diabetes Association ADA-7-13-BS-184 and by the National Heart, Lung, and Blood Institute (NHLBI) R01-HL119215.

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Correspondence to Deneen M. Wellik.

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Editor: Tetsuji Okamoto

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Larsen, B.M., Marty-Santos, L., Newman, M. et al. Hox6 genes modulate in vitro differentiation of mESCs to insulin-producing cells. In Vitro Cell.Dev.Biol.-Animal 52, 974–982 (2016). https://doi.org/10.1007/s11626-016-0066-5

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  • DOI: https://doi.org/10.1007/s11626-016-0066-5

Keywords

  • Hox genes
  • Pancreas development
  • Endocrine cells
  • Insulin-producing cells
  • In vitro ESC differentiation