Conversion of Human Gastric Epithelial Cells to Multipotent Endodermal Progenitors using Defined Small Molecules [DNA methylation]

Endodermal stem/progenitor cells have diverse potential applications in research and regenerative medicine, so a readily available source could have widespread uses. Here we describe derivation of human induced endodermal progenitor cells (hiEndoPCs) from gastrointestinal epithelial cells using a cocktail of defined small molecules along with support from tissue-specific mesenchymal feeders. The hiEndoPCs show clonal expansion in culture and give rise to hepatocytes, pancreatic endocrine cells, and intestinal epithelial cells when treated with defined soluble molecules directing differentiation. The hiEndoPC-derived hepatocytes are able to rescue liver failure in Fah-/-Rag2-/- mice after transplantation, and, unlike hESCs, transplanted hiEndoPCs do not give rise to teratomas. Since human gastric epithelial cells are readily available from donors of many ages, this conversion strategy can generate clonally expandable cell populations with a variety of potential applications, including personalized drug screening and therapeutic strategies for liver failure and diabetes. Overall design: Gastric epithelial cells (GECs) were isolated from human stomach. Human induced endodermal progenitor cells (hiEndoPCs) were reprogrammed from GECs by small molecules. The hiMEP-Heps were differentiated from hiEndoPCs under hepatic differentiation protocol. Fetal-Heps were isolated from aborted fetal liver. We used RNA sequencing and DNA methylation analysis to detail the global gene expression profile of GECs, hiEndoPCs, hiEndoPC-Heps and Fetal-Heps to delineate the difference of these cells.