Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector.
OBJECTIVE
The goal of this study was to modify mesenchymal stem cells (MSCs) cells with a hypoxia-regulated heme oxygenase-1 (HO-1) plasmid to enhance the survival of MSCs in acute myocardial infarction (MI) heart.


BACKGROUND
Although stem cells are being tested clinically for cardiac repair, graft cells die in the ischemic heart because of the effects of hypoxia/reoxygenation, inflammatory cytokines, and proapoptotic factors. Heme oxygenase-1 is a key component in inhibiting most of these factors.


METHODS
Mesenchymal stem cells from bone marrow were transfected with either HO-1 or LacZ plasmids. Cell apoptosis was assayed in vitro after hypoxia-reoxygen treatment. In vivo, 1 x 10(6) of male MSC(HO-1), MSC(LacZ), MSCs, or medium was injected into mouse hearts 1 h after MI (n = 16/group). Cell survival was assessed in a gender-mismatched transplantation model. Apoptosis, left ventricular remodeling, and cardiac function were tested in a gender-matched model.


RESULTS
In the ischemic myocardium, the MSC(HO-1) group had greater expression of HO-1 and a 2-fold reduction in the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling-positive cells compared with the MSC(LacZ) group. At seven days after implantation, the survival MSC(HO-1) was five-fold greater than the MSC(LacZ) group; MSC(HO-1) also attenuated left ventricular remodeling and enhanced the functional recovery of infarcted hearts two weeks after MI.


CONCLUSIONS
A hypoxia-regulated HO-1 vector modification of MSCs enhances the tolerance of engrafted MSCs to hypoxia-reoxygen injury in vitro and improves their viability in ischemic hearts. This demonstration is the first showing that a physiologically inducible vector expressing of HO-1 genes improves the survival of stem cells in myocardial ischemia.
Tang
Yao Liang
YL
Department of Physiology and Biophysics, University of South Florida, St. Petersburg, Florida, USA.
Tang
Yi
Y
Zhang
Y Clare
YC
Qian
Keping
K
Shen
Leping
L
Phillips
M Ian
MI
D003131:Combined Modality Therapy; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006085:Graft Survival; D018840:HSP70 Heat-Shock Proteins; D051547:Heme Oxygenase-1 / Q000235:genetics*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D017202:Myocardial Ischemia / Q000601:surgery*; D010957:Plasmids; D011506:Proteins / Q000235:genetics*
D018840:HSP70 Heat-Shock Proteins; D011506:Proteins; C050087:oxygen-regulated proteins; D051547:Heme Oxygenase-1