Conversion of Human Gastric Epithelial Cells to Multipotent Endodermal Progenitors using Defined Small Molecules

Abstract

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 FahRag2 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.

A molecular roadmap for induced multi-lineage trans-differentiation of fibroblasts by chemical combinations

“…Similar approaches have been used to generate functional cardiac myocytes from both mouse and human fibroblasts [26][27]. Very recently, endodermal progenitors have also been obtained using the chemical reprogramming method [28]. Interestingly, many of these studies shared similar chemicals but described diverse outcomes.…”

Cell sources for regenerative medicine of the liver and endoderm organs: strategies and perspectives

“…In keeping, the small molecule-based reprogramming has attracted much interest due to its safety and efficiency in controlling cell fates (12); this methodology has been successfully used for fibroblast reprogramming into iPS or neurons (13). In this context, the recent paper by Wang et al described a novel approach to generate human induced endodermal progenitor cells (hiEndoPCs); the lineage reprogramming of gastrointestinal epithelial cells was obtained using a cocktail of defined small molecules in association with the support of tissuespecific mesenchymal feeders (1). In terms of transcriptional and epigenetic signatures, hiEndoPCs have been proved to be a particular stage of endodermal progenitor cells which is intermediate between primitive gut-tube and posterior foregut (1).…”

“…In this context, the recent paper by Wang et al described a novel approach to generate human induced endodermal progenitor cells (hiEndoPCs); the lineage reprogramming of gastrointestinal epithelial cells was obtained using a cocktail of defined small molecules in association with the support of tissuespecific mesenchymal feeders (1). In terms of transcriptional and epigenetic signatures, hiEndoPCs have been proved to be a particular stage of endodermal progenitor cells which is intermediate between primitive gut-tube and posterior foregut (1). In vitro, hiEndoPCs clonally expand in culture and have multipotent capability when treated with defined soluble molecules; to this latter regard, hiEndoPCs can give rise to hepatocytes, pancreatic endocrine cells, and intestinal epithelial cells.…”

“…Interestingly, the authors showed that hiEndoPC-derived hepatic cells are fully functional by testing in vitro properties and in vivo capability to rescue liver functions in a murine model of tyrosinemia type I liver disease. Importantly, hiEndoPC maintained a normal karyotype during five continuous passages in vitro and showed no tumors formation over 6 months after subcutaneous transplantation in mice, thus suggesting minimal tumorigenic potential capacity if compared to iPSC or embryonic stem cells (1). Since human gastric epithelial cells are readily available from human donors of many ages, the conversion strategy proposed by Wang and associates can generate clonally expandable cell populations with a variety of potential applications, including disease modeling and personalized drug screening; moreover, their low tumorigenic potentiality makes them more acceptable for future clinical applications.…”

“…In a recent paper, Wang and colleagues showed that a set of defined small molecules plus mesenchymal feeder cells can covert human gastric epithelial cells into induced endodermal progenitors with the capability to differentiate into liver and pancreatic adult parenchymal cells (1). This manuscript could open new perspective in the field of cell therapies for endodermal organs suggesting the stomach as a possible new cell source for the support of liver and pancreatic functions.…”