Journal Article

Bone Marrow Progenitor Cell Therapy-Mediated Paracrine Regulation of Cardiac miRNA-155 Modulates Fibrotic Response in Diabetic Hearts

Krishnamurthy, Prasanna, Mackie, Alexander R., Verma, Suresh K., Abramova, Tatiana V., Vaughan, Erin E., Kishore, Raj, Aiko, Ito

2013

Overview

Diabetes is associated with a higher incidence of myocardial infarction (MI) and increased risk for adverse vascular and fibrogenic events post-MI. Bone marrow-derived progenitor cell (BMPC) therapy has been shown to promote neovascularization, decrease infarct area and attenuate left ventricular (LV) dysfunction after MI. Unlike vascular effects, the anti-fibrosis mechanisms of BMPC, specifically under diabetic conditions, are poorly understood. We demonstrated that intramyocardial delivery of BMPCs in infarcted diabetic db/db mice significantly down-regulates profibrotic miRNA-155 in the myocardium and improves LV remodeling and function. Furthermore, inhibition of paracrine factor hepatocyte growth factor (HGF) signaling in vivo suppressed the BMPC-mediated inhibition of miR-155 expression and the associated protective effect on cardiac fibrosis and function. In vitro studies confirmed that the conditioned media of BMPC inhibited miR-155 expression and profibrotic signaling in mouse cardiac fibroblasts under diabetic conditions. However, neutralizing antibodies directed against HGF blocked these effects. Furthermore, miR-155 over-expression in mouse cardiac fibroblasts inhibited antifibrotic Sloan-Kettering Institute proto-oncogene (Ski) and Ski-related novel gene, non-Alu-containing (SnoN) signaling and abrogated antifibrogenic response of HGF. Together, our data demonstrates that paracrine regulation of cardiac miRNAs by transplanted BMPCs contributes to the antifibrotic effects of BMPC therapy. BMPCs release HGF, which inhibits miR-155-mediated profibrosis signaling, thereby preventing cardiac fibrosis. These data suggest that targeting miR-155 might serve as a potential therapy against cardiac fibrosis in the diabetic heart.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Angiogenesis / Animals / Antibodies / Arthritis / B cells / Biology / Bone marrow / Bone Marrow Transplantation / Care and treatment / Cells, Cultured / Conditioning / Culture Media, Conditioned - pharmacology / Diabetes / Diabetes mellitus / Diabetes Mellitus - genetics / Diabetes Mellitus - metabolism / Diabetes Mellitus - pathology / Diabetes Mellitus - therapy / Diabetics / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Enzymes / Fibroblasts / Fibroblasts - cytology / Fibroblasts - drug effects / Fibroblasts - metabolism / Fibrosis / Gene expression / Gene Expression Regulation / Genetic aspects / Glucose / Growth factors / Health aspects / Heart / Heart diseases / Heart failure / Hematopoietic Stem Cell Transplantation / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - drug effects / Hematopoietic Stem Cells - metabolism / Hepatocyte growth factor / Hepatocyte Growth Factor - metabolism / Hepatocyte Growth Factor - pharmacology / Inhibition / Ischemia / Medical prognosis / Medicine / Mice / MicroRNA / MicroRNAs / MicroRNAs - antagonists & inhibitors / MicroRNAs - genetics / MicroRNAs - metabolism / miRNA / Myocardial infarction / Myocardial Infarction - genetics / Myocardial Infarction - metabolism / Myocardial Infarction - pathology / Myocardial Infarction - therapy / Myocardium / Overexpression / Oxidative stress / Paracrine signalling / Progenitor cells / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Rodents / Signal Transduction / Ski protein / Therapy / Vascularization / Ventricle / Ventricular Dysfunction, Left - genetics / Ventricular Dysfunction, Left - metabolism / Ventricular Dysfunction, Left - pathology / Ventricular Dysfunction, Left - therapy / Ventricular Remodeling - drug effects / Ventricular Remodeling - genetics