title: Mesenchymal stem cells pretreated with delivered Hph-1-Hsp70 protein are protected from hypoxia-mediated cell death and rescue heart functions from myocardial injury.
abstract: Mesenchymal stem cell (MSC) therapy for myocardial injury has inherent limitations due to the poor viability of MSCs after cell transplantation. In this study, we directly delivered Hsp70, a protein with protective functions against stress, into MSCs, using the Hph-1 protein transduction domain ex vivo for high transfection efficiency and low cytotoxicity. Compared to control MSCs in in vitro hypoxic conditions, MSCs delivered with Hph-1-Hsp70 (Hph-1-Hsp70-MSCs) displayed higher viability and anti-apoptotic properties, including Bcl2 increase, reduction of Bax, JNK phosphorylation and caspase-3 activity. Hsp70 delivery also attenuated cellular ATP-depleting stress. Eight animals per group were used for in vivo experiments after occlusion of the left coronary artery. Transplantation of Hph-1-Hsp70-MSCs led to a decrease in the fibrotic heart area, and significantly reduced the apoptotic positive index by 19.5 +/- 2%, compared to no-treatment controls. Hph-1-Hsp70-MSCs were well-integrated into the infarcted host myocardium. The mean microvessel count per field in the infarcted myocardium of the Hph-1-Hsp70-MSC-treated group (122.1 +/- 13.5) increased relative to the MSC-treated group (75.9 +/- 10.4). By echocardiography, transplantation of Hph-1-Hsp70-MSCs resulted in additional increases in heart function, compared to the MSCs-transplanted group. Our results may help formulate better clinical strategies for in vivo MSC cell therapy for myocardial damage.
authors: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Woochul
authors: W
authors: Chang
authors: Byeong-Wook
authors: BW
authors: Song
authors: Soyeon
authors: S
authors: Lim
authors: Heesang
authors: H
authors: Song
authors: Chi Young
authors: CY
authors: Shim
authors: Min-Ji
authors: MJ
authors: Cha
authors: Dong Hyuck
authors: DH
authors: Ahn
authors: Young-Gook
authors: YG
authors: Jung
authors: Dong-Ho
authors: DH
authors: Lee
authors: Ji Hyung
authors: JH
authors: Chung
authors: Ki-Doo
authors: KD
authors: Choi
authors: Seung-Kyou
authors: SK
authors: Lee
authors: Namsik
authors: N
authors: Chung
authors: Sang-Kyou
authors: SK
authors: Lee
authors: Yangsoo
authors: Y
authors: Jang
authors: Ki-Chul
authors: KC
authors: Hwang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000235:genetics / Q000502:physiology*; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D009203:Myocardial Infarction / Q000628:therapy*; D063150:Polycomb Repressive Complex 1; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; C103827:Phc1 protein, mouse; D000255:Adenosine Triphosphate; D063150:Polycomb Repressive Complex 1; D053148:Caspase 3