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Reprogramming fibroblasts into bipotential hepatic stem cells by defined factors.

Bing Yu1, Zhi-Ying He, Pu You

  • 1Department of Cell Biology, Second Military Medical University, Shanghai 200433, China.

Cell Stem Cell
|July 23, 2013
PubMed
Summary

Researchers reprogrammed mouse embryonic fibroblasts into expandable induced hepatic stem cells (iHepSCs) using specific liver organogenesis transcription factors. These iHepSCs can differentiate into both hepatocyte-like cells and cholangiocytes, offering potential for liver disease modeling and tissue engineering.

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Area of Science:

  • Stem Cell Biology
  • Regenerative Medicine
  • Hepatology

Background:

  • Direct reprogramming generates somatic cells from fibroblasts, but stem/progenitor cell reprogramming is limited to blood and neuronal lineages.
  • Previous work generated induced hepatocyte-like (iHep) cells from mouse embryonic fibroblasts (MEFs) using Gata4, Hnf1α, and Foxa3.
  • Limited success in reprogramming stem or progenitor cells for liver lineages necessitates new strategies.

Purpose of the Study:

  • To identify transcription factors sufficient for reprogramming MEFs into expandable, bipotential hepatic stem cells.
  • To evaluate the in vivo differentiation potential of these induced hepatic stem cells (iHepSCs) in liver injury models.
  • To establish a novel strategy for generating both hepatocytes and cholangiocytes for therapeutic and research applications.

Main Methods:

  • Transduction of mouse embryonic fibroblasts (MEFs) with liver organogenesis transcription factors Hnf1β and Foxa3.
  • In vitro expansion and characterization of induced hepatic stem cells (iHepSCs).
  • In vivo assessment of iHepSC engraftment and differentiation in fumarylacetoacetate hydrolase (Fah)-deficient and DDC-induced bile ductular injury mouse models.

Main Results:

  • Hnf1β and Foxa3 successfully reprogrammed MEFs into expandable induced hepatic stem cells (iHepSCs).
  • iHepSCs demonstrated bidirectional differentiation potential into both hepatocytic and cholangiocytic lineages in vitro.
  • In vivo, iHepSCs engrafted and differentiated into hepatocyte-like cells in Fah-deficient livers and cholangiocytes in bile ducts of DDC-injured mice.

Conclusions:

  • Reprogramming MEFs into bipotential, expandable iHepSCs is achievable using Hnf1β and Foxa3.
  • iHepSCs offer a promising source for generating both hepatocytes and cholangiocytes.
  • This lineage conversion strategy advances disease modeling and tissue engineering for liver disorders.