title: Bone marrow progenitor cell therapy-mediated paracrine regulation of cardiac miRNA-155 modulates fibrotic response in diabetic hearts.
abstract: 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.
authors.affiliation: Feinberg Cardiovascular Research Institute, School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Verma
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Mackie
authors.forename: Erin E
authors.initials: EE
authors.lastname: Vaughan
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Abramova
authors.forename: Ito
authors.initials: I
authors.lastname: Aiko
authors.forename: Prasanna
authors.initials: P
authors.lastname: Krishnamurthy
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics
chemical_list: D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D011518:Proto-Oncogene Proteins; C512653:Ski protein, mouse; C486157:Skil protein, mouse; D017228:Hepatocyte Growth Factor
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