A Signaling Crosstalk between BMP9 and HGF/c-Met Regulates Mouse Adult Liver Progenitor Cell Survival

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Addante, Annalisa and Roncero Romero, Cesáreo and Lazcanoiturburu, Nerea and Méndez, Rebeca and Almalé del Barrio, Laura and García Álvaro, María and ten Dijke, Peter and Fabregat, Isabel and Herrera González, Blanca and Sánchez Muñoz, Aránzazu (2020) A Signaling Crosstalk between BMP9 and HGF/c-Met Regulates Mouse Adult Liver Progenitor Cell Survival. Cells, 9 (3). p. 752. ISSN 2073-4409

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Official URL: https://doi.org/10.3390/cells9030752




Abstract

During chronic liver disease, hepatic progenitor cells (HPC, oval cells in rodents) become activated, proliferate, and differentiate into cholangiocytes and/or hepatocytes contributing to the final outcome of the regenerative process in a context-dependent fashion. Here, we analyze the crosstalk between the hepatocyte growth factor (HGF)/c-Met signaling axis, key for liver regeneration, and bone morphogenetic protein (BMP)9, a BMP family ligand that has emerged as a critical regulator of liver pathology. Our results show that HGF/c-Met signaling blocks BMP9-mediated apoptotic cell death, while it potentiates small mothers against decapentaplegic (SMAD)1 signaling triggered by BMP9 in oval cells. Interestingly, HGF-induced overactivation of SMAD1, -5, -8 requires the upregulation of TGF-β type receptor activin receptor-like kinase (ALK)1, and both ALK1 and SMAD1 are required for the counteracting effect of HGF on BMP9 apoptotic activity. On the other hand, we also prove that BMP9 triggers the activation of p38MAPK in oval cells, which drives BMP9-apoptotic cell death. Therefore, our data support a model in which BMP9 and HGF/c-Met signaling axes establish a signaling crosstalk via ALK1 that modulates the balance between the two pathways with opposing activities, SMAD1 (pro-survival) and p38 mitogen-activated protein kinases (p38MAPK; pro-apoptotic), which determines oval cell fate. These data help delineate the complex signaling network established during chronic liver injury and its impact on the oval cell regenerative response.


Item Type:Article
Uncontrolled Keywords:BMP9; HGF; hepatic oval cell; apoptosis; signaling crosstalk; ALK1; SMAD1; p38MAPK
Subjects:Medical sciences > Pharmacy > Molecular biology
Medical sciences > Pharmacy > Biochemistry
ID Code:67104
Deposited On:27 Jul 2021 13:54
Last Modified:18 Aug 2021 11:20

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