Sry HMG box protein 9-positive (Sox9+) epithelial cell adhesion molecule-negative (EpCAM-) biphenotypic cells derived from hepatocytes are involved in mouse liver 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 4α-positive (HNF4α(+)) 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® 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 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.
From the Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556.
Naoki
N
Tanimizu
Yuji
Y
Nishikawa
Norihisa
N
Ichinohe
Haruhiko
H
Akiyama
Toshihiro
T
Mitaka
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002454:Cell Differentiation; D000071858:Epithelial Cell Adhesion Molecule; D049452:Green Fluorescent Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D008115:Liver Regeneration; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D010641:Phenotype; D011725:Pyridines / Q000737:chemistry; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology
C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D011725:Pyridines; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D049452:Green Fluorescent Proteins
Biphenotypic Cells; Cell Differentiation; Cell Polarity; Ductular Reaction; Hepatocyte; Liver; Liver Stem/Progenitor Cells; Regeneration