title: Effects of mesenchymal stem cells on matrix metalloproteinase synthesis in cardiac fibroblasts.
abstract: Mesenchymal stem cell (MSC) transplantation has been known to decrease matrix metalloproteinase (MMP) synthesis in myocardium after myocardial infarction (MI) and improve ventricular remodeling; however, the underlying mechanisms are unclear. This study investigated the effects of MSC on MMP synthesis in cardiac fibroblasts (CFs) through paracrine actions. CFs were cultured under hypoxic (0.5% pO(2)) conditions for 24 h before co-culture with MSCs or hypoxia-preconditioned MSCs (H-MSCs) in transwell plates. CFs and MSCs/H-MSCs shared a medium with or without erythropoietin (EPO) neutralizing antibody (EPOAb) or EPO-soluble receptor (EPOsR). The results showed that protein expression and activity of MMP-2 and membrane type 1-MMP, but not MMP-9, in CFs were significantly increased in response to hypoxia and decreased after co-culture with MSCs or H-MSCs. Hypoxia up-regulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2 of CFs which was down-regulated after CFs' co-culture with MSCs. Tissue inhibitors of metalloproteinases-1 (TIMP-1) in CFs was decreased after hypoxia and increased when co-cultured with MSCs or H-MSCs. Exogenous EPOAb or EPOsR partially inhibited MSCs' effect on MMP-2 expression and activity in CFs. The present findings suggested that MSCs influence MMP/TIMP expression in CFs via the ERK1/2 pathway and EPO acts as a key factor in the paracrine actions of MSCs.
authors.affiliation: Cardiovascular Center, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310009, PR China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Wang
authors.forename: Xinyang
authors.initials: X
authors.lastname: Hu
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Xie
authors.forename: Aina
authors.initials: A
authors.lastname: He
authors.forename: Xianbao
authors.initials: X
authors.lastname: Liu
authors.forename: Jian-an
authors.initials: JA
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005347:Fibroblasts / Q000201:enzymology; D000860:Hypoxia / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D009206:Myocardium / Q000166:cytology* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9