Effects of mesenchymal stem cells on matrix metalloproteinase synthesis in cardiac fibroblasts.

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.