Sry HMG box protein 9-positive (Sox9+) epithelial cell adhesion molecule-negative (EpCAM-) biphenotypic cells derived from hepatocytes are involved in mouse liver regeneration [Molecular Bases of Disease]

January 30th, 2014 by Tanimizu, N., Nishikawa, Y., Ichinohe, N., Akiyama, H., Mitaka, T.

It has been shown that mature hepatocytes (MHs) 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 4α-positive (HNF4α+) biphenotypic cells showing hepatocytic morphology appeared near EpCAM+ ductular structures in the livers of 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) containing diet fed mice. When Mx1-Cre/ROSA mice, which were injected with Poly(I:C) to label MHs, were fed with 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 incident 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 without expressing EpCAM. These results suggest that Sox9+EpCAM- cells maintaining biphenotypic status can establish cholangiocyte-type polarity. Interestingly, we found that part of Sox9+ cells surrounded luminal spaces in DDC injured liver while they expressed HNF4α. 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.
  • Posted in Journal of Biological Chemistry, Publications
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