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.
Highlights
Under chronic liver disease (CLD), hepatic progenitor cells (HPC, oval cells in rodents) become activated, expand into liver parenchyma and differentiate into cholangiocytes and/or hepatocytes, trying to compensate for the cellular loss and to help maintain liver homeostasis; contributing to sustain liver regeneration during hepatic disorders [1,2]
Since our previous data demonstrated that BMP9 induces apoptosis in oval cells, we first analyzed flx/flxcells, Sincecould our previous data demonstrated that BMP9 in oval first whether hepatocyte growth factor (HGF)
We have previously demonstrated that activin receptor-like kinase-2 (ALK2) and not Activin receptor-like kinase 1 (ALK1) is the transforming growth factor β (TGF-β) we aimed at characterizing the mechanism mediating BMP9-HGF signaling interaction
Summary
Under chronic liver disease (CLD), hepatic progenitor cells (HPC, oval cells in rodents) become activated, expand into liver parenchyma and differentiate into cholangiocytes and/or hepatocytes, trying to compensate for the cellular loss and to help maintain liver homeostasis; contributing to sustain liver regeneration during hepatic disorders [1,2]. Studies on the regulation of the HPCs are required to better delineate specific factors and molecular mechanisms that direct these cells towards a pro-regenerative or pro-fibrogenic status In this regard, it is well established that hepatocyte growth factor (HGF) and its tyrosine kinase receptor, c-Met, are critical for a successful oval cell-mediated regenerative response after chronic liver damage in mice [6]. In spite of the important advances achieved regarding the functions and mechanisms of action of the HGF/c-Met pathway in oval cells, it is still poorly known how HGF interplays with other factors present in the damaged liver to impact on oval cell biology In this sense, we have just uncovered a coordinated and balanced action of HGF and transforming growth factor β (TGF-β) pathways for the regulation of the HPC/oval cell epithelial–mesenchymal transition response [7]. HGF-interplays or crosstalks with other factors remain to be identified
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