Direct Conversion of Mouse Fibroblasts into Cholangiocyte Progenitor Cells

Kyung Tae Lim, Jonghun Kim, Seon In Hwang, Ludi Zhang, Heonjong Han, Dasom Bae, Kee Pyo Kim, Yi Ping Hu, Hans R. Schöler, Insuk Lee, Lijian Hui, Dong Wook Han

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2 Citations (Scopus)

Abstract

Disorders of the biliary epithelium, known as cholangiopathies, cause severe and irreversible liver diseases. The limited accessibility of bile duct precludes modeling of several cholangiocyte-mediated diseases. Therefore, novel approaches for obtaining functional cholangiocytes with high purity are needed. Previous work has shown that the combination of Hnf1β and Foxa3 could directly convert mouse fibroblasts into bipotential hepatic stem cell-like cells, termed iHepSCs. However, the efficiency of converting fibroblasts into iHepSCs is low, and these iHepSCs exhibit extremely low differentiation potential into cholangiocytes, thus hindering the translation of iHepSCs to the clinic. Here, we describe that the expression of Hnf1α and Foxa3 dramatically facilitates the robust generation of iHepSCs. Notably, prolonged in vitro culture of Hnf1α- and Foxa3-derived iHepSCs induces a Notch signaling-mediated secondary conversion into cholangiocyte progenitor-like cells that display dramatically enhanced differentiation capacity into mature cholangiocytes. Our study provides a robust two-step approach for obtaining cholangiocyte progenitor-like cells using defined factors. In this article, Han and colleagues revisited the roles of HepSC-specific factors and found that Hnf1α and Foxa3 facilitate the robust conversion into iHepSCs displaying a relatively closer transcriptional pattern with LEPCs. The prolonged in vitro culture of iHepSCs induces Notch-mediated secondary conversion into iCPCs, which could efficiently be differentiated into mature cholangiocytes.

Original languageEnglish
Pages (from-to)1522-1536
Number of pages15
JournalStem Cell Reports
Volume10
Issue number5
DOIs
Publication statusPublished - 2018 May 8

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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    Lim, K. T., Kim, J., Hwang, S. I., Zhang, L., Han, H., Bae, D., Kim, K. P., Hu, Y. P., Schöler, H. R., Lee, I., Hui, L., & Han, D. W. (2018). Direct Conversion of Mouse Fibroblasts into Cholangiocyte Progenitor Cells. Stem Cell Reports, 10(5), 1522-1536. https://doi.org/10.1016/j.stemcr.2018.03.002