Abstract
Hepatocytes perform most of the functions of the liver and are considered terminally differentiated cells. Recently, it has been suggested that hepatocytes might have the potential to transdifferentiate or dedifferentiate under physiological or pathological conditions in vivo. Epithelial-mesenchymal transition of hepatocytes in liver fibrosis has also been proposed. However, these findings have not been fully confirmed. In this study, hepatocytes were genetically labelled for cell fate tracing using lacZ via the tamoxifen-induced CreERT/loxP system. After induction with tamoxifen, alb + cells were permanently marked by lacZ expression, and all progeny lacZ + cells were derived from a single source with no interference. We did not observe transdifferentiation or dedifferentiation of hepatocytes into cholangiocytes or hepatic progenitor cells under conditions of liver homeostasis or following a 2/3 partial hepatectomy. Meanwhile, lacZ/OPN-positive cells were observed in livers of 3,5-diethoxycarbonyl-1,4-dihydrocollidine-fed mice, and lacZ/alpha-smooth muscle actin-positive cells were detected in carbon tetrachloride-induced chronic liver injury models. These results suggested that some existing differentiated alb + cells might have the potential of transdifferentiation/dedifferentiation or epithelial-to-mesenchymal transition in vivo in some liver injury models, but the proportion of these alb + cells in liver was very low, and their significance and actual function during the pathological process remains to be elucidated.
Highlights
The liver is considered unique among adult mammalian organs because of its incredible regenerative capability
Livers were double immunostained for lacZ and the hepatocyte marker albumin (Alb), the cholangiocyte marker cytokeratin 19 (Ck19), the hepatic stellate cell (HSC) marker alpha-smooth muscle actin (α-sma), or the stem cell marker osteopontin (OPN)
We calculated the ratio of lacZ-positive cells in alb, Ck19, α-sma, or OPN-positive cellsand found the ratio of lacZ + /alb + cells in alb + cells (94.31% ± 2.81%) was significantly higher than that in Ck19 + (1.76% ± 1.25%), α-sma + (0.00% ± 0.00%), or OPN + (0.00% ± 0.00%) cells (Fig. 1d)
Summary
The liver is considered unique among adult mammalian organs because of its incredible regenerative capability. In a carbon tetrachloride (CCl4)-induced liver injury model, hepatocytes are considered ‘accomplices’ in progressive fibrosis by expressing TGF-β and fibromodulin, which promote fibrosis in vivo[6,7]. It remains unclear whether hepatocytes generate their progeny cells via direct proliferation or whether they require a process of dedifferentiation into progenitor cells. We used the albumin (Alb)-CreERT/Rosa26-LsL-LacZ system to trace hepatocytes and their progeny cells during liver homeostasis or indifferent liver repair processes in vivo via the lacZ tag. The proportion of these hepatocyte-derived cells in liver was very low, and their significance and actual function during the pathological process remains to be elucidated
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