title: Bcl-2 engineered MSCs inhibited apoptosis and improved heart function.
abstract: Engraftment of mesenchymal stem cells (MSCs) derived from adult bone marrow has been proposed as a potential therapeutic approach for postinfarction left ventricular dysfunction. However, limited cell viability after transplantation into the myocardium has restricted its regenerative capacity. In this study, we genetically modified MSCs with an antiapoptotic Bcl-2 gene and evaluated cell survival, engraftment, revascularization, and functional improvement in a rat left anterior descending ligation model via intracardiac injection. Rat MSCs were manipulated to overexpress the Bcl-2 gene. In vitro, the antiapoptotic and paracrine effects were assessed under hypoxic conditions. In vivo, the Bcl-2 gene-modified MSCs (Bcl-2-MSCs) were injected after myocardial infarction. The surviving cells were tracked after transplantation. Capillary density was quantified after 3 weeks. The left ventricular function was evaluated by pressure-volume loops. The Bcl-2 gene protected MSCs against apoptosis. In vitro, Bcl-2 overexpression reduced MSC apoptosis by 32% and enhanced vascular endothelial growth factor secretion by more than 60% under hypoxic conditions. Transplantation with Bcl-2-MSCs increased 2.2-fold, 1.9-fold, and 1.2-fold of the cellular survival at 4 days, 3 weeks, and 6 weeks, respectively, compared with the vector-MSC group. Capillary density in the infarct border zone was 15% higher in Bcl-2-MSC transplanted animals than in vector-MSC treated animals. Furthermore, Bcl-2-MSC transplanted animals had 17% smaller infarct size than vector-MSC treated animals and exhibited functional recovery remarkably. Our current findings support the premise that transplantation of antiapoptotic gene-modified MSCs may have values for mediating substantial functional recovery after acute myocardial infarction.
authors.affiliation: Department of Cardiac Surgery, University Rostock, Schillingallee 69, Rostock, Germany.
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Li
authors.forename: Nan
authors.initials: N
authors.lastname: Ma
authors.forename: Lee-Lee
authors.initials: LL
authors.lastname: Ong
authors.forename: Catharina
authors.initials: C
authors.lastname: Nesselmann
authors.forename: Christian
authors.initials: C
authors.lastname: Klopsch
authors.forename: Yury
authors.initials: Y
authors.lastname: Ladilov
authors.forename: Dario
authors.initials: D
authors.lastname: Furlani
authors.forename: Christoph
authors.initials: C
authors.lastname: Piechaczek
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Moebius
authors.forename: Karola
authors.initials: K
authors.lastname: Lützow
authors.forename: Andreas
authors.initials: A
authors.lastname: Lendlein
authors.forename: Christof
authors.initials: C
authors.lastname: Stamm
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.forename: Gustav
authors.initials: G
authors.lastname: Steinhoff
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation; D015687:Cell Hypoxia / Q000235:genetics; D002478:Cells, Cultured; D019254:Genes, bcl-2; D006321:Heart / Q000502:physiology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology*; D009203:Myocardial Infarction / Q000628:therapy; D030781:Organisms, Genetically Modified; D051381:Rats; D011917:Rats, Inbred Lew; D012038:Regeneration; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A