title: Liver extracellular matrix promotes BM-MSCs hepatic differentiation and reversal of liver fibrosis through activation of integrin pathway.
abstract: 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. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: State Key Laboratory of Military Stomatology, Centre for Tissue Engineering, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi, China.|Research and Development Centre for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Huanjing
authors.initials: H
authors.lastname: Bi
authors.affiliation: State Key Laboratory of Military Stomatology, Centre for Tissue Engineering, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi, China.|Research and Development Centre for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Leiguo
authors.initials: L
authors.lastname: Ming
authors.affiliation: State Key Laboratory of Military Stomatology, Centre for Tissue Engineering, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi, China.|Research and Development Centre for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Ruiping
authors.initials: R
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Military Stomatology, Centre for Tissue Engineering, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi, China.|Research and Development Centre for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Hailang
authors.initials: H
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Military Stomatology, Centre for Tissue Engineering, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi, China.|Research and Development Centre for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China.|State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Military Stomatology, Centre for Tissue Engineering, School of Stomatology, the Fourth Military Medical University, Xi'an, Shaanxi, China.|Research and Development Centre for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, China.|State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000818:Animals; D002413:Cations, Divalent / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology*; D008345:Manganese / Q000494:pharmacology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D034421:Sus scrofa
chemical_list: D002413:Cations, Divalent; D016023:Integrins; D008345:Manganese
keywords: bone marrow mesenchymal stem cells; cell transplantation; extracellular matrix; hepatic differentiation; liver fibrosis; mesenchymal stem cells