title: Paracrine effect of Wnt11-overexpressing mesenchymal stem cells on ischemic injury.
abstract: Our previous studies have suggested that transduction of Wnt11 directly increases bone marrow-derived mesenchymal stem cells (MSCs) differentiation into cardiac phenotypes. In this study, we investigated whether Wnt11 enhances MSC-mediated cardioprotection via paracrine fashion after acute ischemia. MSCs were harvested from male rat bone marrow and transduced with Wnt11 (MSC(Wnt11)). An acute myocardial infarction model in rats was developed by ligation of the left anterior descending coronary artery. MSC(Wnt11) were transplanted into the peri-infarct region after acute myocardial infarction. To mimic ischemic injury, cultured cardiomyocytes (CMs) isolated from neonatal ventricles were exposed to hypoxia. ELISA studies indicated that the release of Wnt11 (3.45-fold) as well as transforming growth factor-β2 (TGFβ2) (1.5-fold) was significantly increased from MSC(Wnt11) compared with transduced control MSC (MSC(Null)). Hypoxia-induced apoptosis and cell death was significantly reduced when CM were co-cultured with MSC(Wnt11) in a dual chamber system. The cell protection mediated by MSC(Wnt11) was mimicked by treating CM with conditioned medium obtained from MSC(Wnt11) and abrogated by Wnt11- and TGFβ2 neutralizing antibodies. Further, animals receiving MSC(Wnt11) showed a significant improvement in cardiac contractile function as assessed by echocardiography. Masson trichrome and TUNEL staining showed a significant reduction in infarct size and apoptosis of CM in MSC(Wnt11)-treated animals. Transplantation of MSC(Wnt11) improved cardiac function. The release of Wnt11 and other factors from transplanted MSC(Wnt11) is more likely responsible for protection of native CM at risk.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA.
authors.forename: Shi
authors.initials: S
authors.lastname: Zuo
authors.forename: W Keith
authors.initials: WK
authors.lastname: Jones
authors.forename: Hongxia
authors.initials: H
authors.lastname: Li
authors.forename: Zhisong
authors.initials: Z
authors.lastname: He
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Pasha
authors.forename: Yueting
authors.initials: Y
authors.lastname: Yang
authors.forename: Yigang
authors.initials: Y
authors.lastname: Wang
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ashraf
authors.forename: Meifeng
authors.initials: M
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D009200:Myocardial Contraction / Q000235:genetics; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D019899:Paracrine Communication; D051381:Rats; D017207:Rats, Sprague-Dawley; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism; D014184:Transplantation, Homologous; D051153:Wnt Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D053781:Transforming Growth Factor beta2; D051153:Wnt Proteins; C502412:Wnt11 protein, rat