Direct Conversion of Mouse Fibroblasts into Cholangiocyte Progenitor Cells

• Published in: Stem cell reports Vol. 10; no. 5; pp. 1522 - 1536
• Main Authors: Lim, Kyung Tae, Kim, Jonghun, Hwang, Seon In, Zhang, Ludi, Han, Heonjong, Bae, Dasom, Kim, Kee-Pyo, Hu, Yi-Ping, Schöler, Hans R., Lee, Insuk, Hui, Lijian, Han, Dong Wook
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.05.2018; Elsevier
• Subjects: Animals; Biliary Tract - cytology; Cell Differentiation; cholangiocyte progenitor cells; direct conversion; Epithelial Cells - cytology; Epithelial Cells - metabolism; Fibroblasts - cytology; Fibroblasts - metabolism; hepatic stem cells; Hepatocyte Nuclear Factor 1-alpha - metabolism; Hepatocyte Nuclear Factor 3-gamma - metabolism; Hepatocytes - cytology; Hepatocytes - metabolism; Liver - cytology; Mice, Inbred C57BL; Notch signal; Receptors, Notch - metabolism; Signal Transduction; Stem Cells - cytology; Stem Cells - metabolism; Transcription, Genetic; cholangiocyte progenitor cells; direct conversion; hepatic stem cells; Notch signal
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2018.03.002

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. [Display omitted] •Hnf1α and Foxa3 (1a3) induce robust generation of iHepSCs from fibroblasts•1a3-derived iHepSCs are transcriptionally closer to LEPCs than 1b3-iHepSCs•Prolonged culture induces Notch-mediated secondary conversion into iCPCs•This study provides the robust two-step approach for obtaining iCPCs 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.