Liver extracellular matrix promotes BM-MSCs hepatic differentiation and reversal of liver fibrosis through activation of integrin pathway.

In cell-based therapies for liver injuries, the clinical outcomes are closely related to the surrounding microenvironment of the transplanted bone marrow mesenchymal stem cells (BM-MSCs). However, whether liver-specific ECM (L-ECM), as one of major microenvironment signals, could regulate the therapeutic effect of BM-MSCs through changing their biological characteristics is unclear. This study aimed to investigate the hepatogenicity and underlying mechanism of L-ECM as well as its potential regulative role in the MSC-based liver recovery. L-ECM was prepared by homogenization of decellularized whole porcine liver. After three-dimensional culture with or without the presence of L-ECM, BM-MSCs expressed hepatocyte-specific genes and proteins in an L-ECM concentration-dependent manner. Further analysis showed that L-ECM could activate specific types of integrins (ITGs) as well as their downstream signalling pathways. When the cell/ECM interaction was enhanced by incorporating BM-MSCs with Mn2+ , ITGs were activated and the hepatogenic capacity of L-ECM was improved. The regeneration of rat livers from either acute or chronic fibrosis could also be accelerated after transplantation of Mn2+ -treated BM-MSCs. L-ECM therefore promotes hepatic differentiation of BM-MSCs via the ITG pathway and plays a therapeutically beneficial role for stem cell-based liver regeneration.