Dataset Information

Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin-?v?6 integrin in liver fibrosis.

ABSTRACT: Hepatocytes undergo the metaplasia into ductal biliary epithelial cells (BECs) in response to chronic injury, and subsequently contribute to liver regeneration. The mechanism underlying hepatocyte-to-ductal metaplasia has not been explored until now. In mouse models of liver fibrosis, a florid BEC response was observed in fibrotic liver, and the depletion of myofibroblasts attenuated BEC expansion remarkably. Then, in hepatocyte fate-tracing mouse model, we demonstrated the conversion of mature hepatocytes into ductal BECs in fibrotic liver, and the depletion of myofibroblasts diminished the hepatocyte-to-ductal metaplasia. Finally, the mechanism underlying the metaplasia was investigated. Myofibroblasts secreted laminin-rich extracellular matrix, and then laminin induced hepatocyte-to-ductal metaplasia through ?v?6 integrin. Therefore, our results demonstrated myofibroblasts induce the conversion of mature hepatocytes into ductal BECs through laminin-?v?6 integrin, which reveals that the strategy improve regeneration in fibrotic liver through the modification of specific microenvironment.

SUBMITTER: Xu T

PROVIDER: S-EPMC7090046 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin-ɑvβ6 integrin in liver fibrosis.

Xu Ting T Lu Zhiwen Z Xiao Zhuanglong Z Liu Fang F Chen Yuhua Y Wang Zhijun Z Zhu Shenghua S Song Yuhu Y Song Yuhu Y

Cell death & disease 20200323 3

Hepatocytes undergo the metaplasia into ductal biliary epithelial cells (BECs) in response to chronic injury, and subsequently contribute to liver regeneration. The mechanism underlying hepatocyte-to-ductal metaplasia has not been explored until now. In mouse models of liver fibrosis, a florid BEC response was observed in fibrotic liver, and the depletion of myofibroblasts attenuated BEC expansion remarkably. Then, in hepatocyte fate-tracing mouse model, we demonstrated the conversion of mature ...[more]

PMID: 32251270

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Project description:BackgroundCancer-associated fibroblasts (CAFs) are among the most prominent cells during the desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC). However, CAFs are heterogeneous and the precise origins are not fully elucidated. This study aimed to explore whether monocytes can transdifferentiate into fibroblasts in PDAC and evaluate the clinical significance of this event.MethodsCD14+ monocytes were freshly isolated from human peripheral blood. Immunofluorescence, reverse transcription-quantitative PCR, western blot, flow cytometry and enzyme-linked immunosorbent assay were used to detect the expression of αSMA, fibronectin, and other relevant molecules. In addition, latex beads with a mean particle size of 2.0 µm were used to assess the phagocytic capacity. Moreover, RNA sequencing (RNA-seq) was performed to identify the differences induced by H2 O2 and the underlying mechanisms.ResultsImmunofluorescence identified αSMA and fibroblast-specific protein 1 expression by tumor-associated macrophages in PDAC. The in vitro experiment revealed that oxidative stress (H2 O2 or radiation) induced monocyte-to-myofibroblast transdifferentiation (MMT), as identified by upregulated αSMA expression at both the RNA and protein levels. In addition, compared with freshly isolated monocytes, human monocyte-derived macrophages increased fibronectin expression. RNA-seq analysis identified p53 activation and other signatures accompanying this transdifferentiation; however, the p53 stabilizer nutlin-3 induced αSMA expression through reactive oxygen species generation but not through the p53 transcription/mitochondria-dependent pathway, whereas the p38 inhibitor SB203580 could partially inhibit αSMA expression. Finally, MMT produced a unique subset of CAFs with reduced phagocytic capacity that could promote the proliferation of pancreatic cancer cells.ConclusionsOxidative stress in the tumor microenvironment could induce MMT in PDAC, thus inducing reactive stroma, modulating immunosuppression, and promoting tumor progression. Reducing oxidative stress may be a promising future therapeutic regimen.

Dataset Information

Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin-?v?6 integrin in liver fibrosis.

Publications

Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin-ɑvβ6 integrin in liver fibrosis.

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