Generation of hepatocyte- and endocrine pancreatic-like cells from human induced endodermal progenitor cells

PLoS One. 2018 May 11;13(5):e0197046. doi: 10.1371/journal.pone.0197046. eCollection 2018.

Abstract

Multipotent Adult Progenitor Cells (MAPCs) are one potential stem cell source to generate functional hepatocytes or β-cells. However, human MAPCs have less plasticity than pluripotent stem cells (PSCs), as their ability to generate endodermal cells is not robust. Here we studied the role of 14 transcription factors (TFs) in reprogramming MAPCs to induced endodermal progenitor cells (iENDO cells), defined as cells that can be long-term expanded and differentiated to both hepatocyte- and endocrine pancreatic-like cells. We demonstrated that 14 TF-iENDO cells can be expanded for at least 20 passages, differentiate spontaneously to hepatocyte-, endocrine pancreatic-, gut tube-like cells as well as endodermal tumor formation when grafted in immunodeficient mice. Furthermore, iENDO cells can be differentiated in vitro into hepatocyte- and endocrine pancreatic-like cells. However, the pluripotency TF OCT4, which is not silenced in iENDO cells, may contribute to the incomplete differentiation to mature cells in vitro and to endodermal tumor formation in vivo. Nevertheless, the studies presented here provide evidence that reprogramming of adult stem cells to an endodermal intermediate progenitor, which can be expanded and differentiate to multiple endodermal cell types, might be a valid alternative for the use of PSCs for creation of endodermal cell types.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation*
  • Cellular Reprogramming Techniques
  • Endoderm / cytology
  • Endoderm / metabolism*
  • Hepatocytes / cytology
  • Hepatocytes / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism*
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*

Grant support

R.S. was supported by the Dutch Diabetes Foundation (2008.50.003), the Netherlands and KU Leuven; S.D. was supported by pre-doctoral scholaship from KU Leuven; P.R. was supported by Research Foundation Flanders (FWO); M.K. was supported by H2020-MSCA- (IF)-657701; N.H. was Funded by IWT (SB-121396); S.K. is supported by the Wellcome Trust/DBT India Alliance Fellowship (IA/I/15/2/502061) and intramural grant from IISER TVM; and Centre of Excellence funding from the KU Leuven to C.M.V. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.