期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 11, 页码 7589-7598出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.517243
关键词
Cell Differentiation; Cell Polarity; Hepatocyte; Liver; Regeneration; Biphenotypic Cells; Ductular Reaction; Liver Stem; Progenitor Cells
资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan [22790386, 25460271, 21390365, 24390304]
- Grants-in-Aid for Scientific Research [24659591, 25282135, 22790386, 25293289, 25460271, 25670186, 24390092, 24390304, 21390365] Funding Source: KAKEN
Background: Biphenotypic hepatocytes expressing Sox9 emerge upon liver injuries associated with ductular reaction. Results: Sox9(+) biphenotypic hepatocytes are derived from mature hepatocytes (MHs). Some of them are incorporated into ductular structures, whereas they efficiently differentiate to functional hepatocytes. Conclusion: Biphenotypic hepatocytes not only terminally convert to cholangiocytes but also differentiate back to MHs. Significance: Mature epithelial cells can show plasticity upon severe injuries and contribute to regeneration. It has been shown that mature hepatocytes compensate tissue damages not only by proliferation and/or hypertrophy but also by conversion into cholangiocyte-like cells. We found that Sry HMG box protein 9-positive (Sox9(+)) epithelial cell adhesion molecule-negative (EpCAM(-)) hepatocyte nuclear factor 4-positive (HNF4(+)) biphenotypic cells showing hepatocytic morphology appeared near EpCAM(+) ductular structures in the livers of mice fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing diet. When Mx1-Cre:ROSA mice, which were injected with poly(I:C) to label mature hepatocytes, were fed with the DDC diet, we found LacZ(+)Sox9(+) cells near ductular structures. Although Sox9(+)EpCAM(-) cells adjacent to expanding ducts likely further converted into ductular cells, the incidence was rare. To know the cellular characteristics of Sox9(+)EpCAM(-) cells, we isolated them as GFP(+)EpCAM(-) cells from DDC-injured livers of Sox9-EGFP mice. Sox9(+)EpCAM(-) cells proliferated and could differentiate to functional hepatocytes in vitro. In addition, Sox9(+)EpCAM(-) cells formed cysts with a small central lumen in collagen gels containing Matrigel (R) without expressing EpCAM. These results suggest that Sox9(+)EpCAM(-) cells maintaining biphenotypic status can establish cholangiocyte-type polarity. Interestingly, we found that some of the Sox9(+) cells surrounded luminal spaces in DDC-injured liver while they expressed HNF4. Taken together, we consider that in addition to converting to cholangiocyte-like cells, Sox9(+)EpCAM(-) cells provide luminal space near expanded ductular structures to prevent deterioration of the injuries and potentially supply new hepatocytes to repair damaged tissues.
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