Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration

Significance The precise roles of E-cadherin in the liver and liver carcinogenesis are still unknown. Here we show that mice lacking E-cadherin in the liver develop spontaneous periportal inflammation via an impaired intrahepatic biliary network, as well as periductal fibrosis, which resembles primary sclerosing cholangitis. Inducible gene knockout studies identified E-cadherin loss in biliary epithelial cells as a causal factor of cholangitis induction, and dysregulated E-cadherin expression was also seen in patients with primary sclerosing cholangitis. E-cadherin loss also significantly accelerates genetically and chemically engineered liver cancer through epithelial–mesenchymal transition, up-regulation of stem cell markers, and ERK activation. Thus, E-cadherin plays critical roles in maintaining homeostasis and suppressing carcinogenesis in the liver.

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“…S1B). These results are consistent with recent reports of Cre expression in hepatocytes and interlobular BECs of Alb-Cre mice (16).…”

Section: Significancesupporting

confidence: 94%

Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis

Nakagawa

Hikiba

Hirata

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

109

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“…Intriguingly, fate‐tracing studies showed recombination additionally in the venous ECs, suggesting Lyve1 expression occurring at some developmental stage in the venous ECs. Indeed, such analogies exist, for example, the albumin‐cre transgenic line recombines floxed genes in hepatocytes and cholangiocytes despite albumin expression only in adult hepatocytes 27, 28. This occurs due to the temporal expression of the albumin gene in hepatoblasts during development, which gives rise to both hepatocytes and cholangiocytes 6, 27.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Wnts regulate β‐catenin signaling in murine liver zonation and regeneration: A sequel to the Wnt–Wnt situation

Preziosi

Okabe

Poddar

et al. 2018

Hepatology Communications

113

156

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β‐Catenin in hepatocytes, under the control of Wnts, regulates pericentral gene expression. It also contributes to liver regeneration (LR) after partial hepatectomy (PH) by regulating cyclin‐D1 gene expression as shown in the β‐catenin and Wnt coreceptors low‐density lipoprotein receptor‐related protein 5/6 conditional knockouts (KO). However, conditional deletion of Wntless (Wls), required for Wnt secretion, in hepatocytes, cholangiocytes, or macrophages lacked any impact on zonation, while Wls deletion in macrophages only marginally affected LR. Here, we address the contribution of hepatic endothelial cells (ECs) in zonation and LR by characterizing EC‐Wls‐KO generated by interbreeding Wls‐floxed and lymphatic vessel endothelial hyaluronan receptor (Lyve1)‐cre mice. These mice were also used to study LR after PH. While Lyve1 expression in adult liver is limited to sinusoidal ECs only, Lyve1‐cre mice bred to ROSA26‐Stopflox/flox‐enhanced yellow fluorescent protein (EYFP) mice showed EYFP labeling in sinusoidal and central vein ECs. EC‐Wls‐KO mice showed decreased liver weights; lacked glutamine synthetase, cytochrome P450 2e1, and cytochrome P450 1a2; and were resistant to acetaminophen‐induced liver injury. After PH, EC‐Wls‐KO showed quantitative and qualitative differences in cyclin‐D1 expression at 24‐72 hours, which led to a lower hepatocyte proliferation at 40 hours but a rebound increase by 72 hours. ECs and macrophages isolated from regenerating livers at 12 hours showed significant up‐regulation of Wnt2 and Wnt9b messenger RNA; these are the same two Wnts involved in baseline β‐catenin activity in pericentral hepatocytes. Conclusion: At baseline, ECs secrete Wnt proteins essential for β‐catenin activation in pericentral hepatocytes. During LR, sinusoidal and central vein ECs and secondarily macrophages secrete Wnt2, while predominantly central vein ECs and secondarily macrophages are the likely source of Wnt9b. This process spatiotemporally regulates β‐catenin activation in hepatocytes to induce cell proliferation. (Hepatology Communications 2018;2:845‐860)

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“…We also suggested that the centrilobular ductular reaction induced by chronic CCl 4 injury might be reversible. Although the origin of ductular cells in the ductular reaction is still debated and a recent work did not find evidence for formation of ductular cells from hepatocytes, 36 Matrigel-coated surfaces (n=4). *P value < 0.05, **P value < 0.01, compared with Dex (unpaired two-tailed t-test); # P value < 0.01, compared with control (unpaired two-tailed t-test).…”

Section: Discussionmentioning

confidence: 99%

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Sone

Nishikawa

Nagahama

et al. 2012

The American Journal of Pathology

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We previously demonstrated that mature rat hepatocytes transdifferentiate to bile ductular cells when cultured in a three-dimensional collagen-rich matrix. Here, we show that the phenotype of transdifferentiated hepatocytes can be reversed by modulating culture conditions. Spheroidal aggregates of hepatocytes were cultured within a collagen gel matrix in the presence of serum and tumor necrosis factor-α. Spheroids transformed into ductular structures composed of small cuboidal cells, lost the expression of hepatocytic markers, while aberrantly expressed bile ductular markers. The transdifferentiated cells were then retrieved from the gels, plated on Matrigel-coated surfaces, and cultured in serum-free media. Cells spontaneously formed spheroidal aggregates and recovered hepatocytic phenotype. While Dexamethasone (Dex), which suppressed the phosphorylation of ERK and Jun N-terminal kinase, facilitated the recovery, the combination with interleukin-6 or oncostatin M resulted in the recovery of HNF-4α protein expression and the typical hepatocytic morphology and a decrease in the expression of bile ductular markers. A cDNA microarray analysis revealed that the hepatocyte-specific mRNA expression profile was recovered in these cells. Our results demonstrate that hepatocytes are able to recover their phenotypes following bile ductular transdifferentiation, suggesting that hepatocytic and bile ductular phenotypes may be mutually reversible.4

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Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration

Cited by 395 publications

References 62 publications

Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis

Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis

Endothelial Wnts regulate β‐catenin signaling in murine liver zonation and regeneration: A sequel to the Wnt–Wnt situation

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

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