Mesenchymal stem cells from bone marrow were transfected with either HO-1 or LacZ plasmids... Read More >
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... Read More >
Improved Graft Mesenchymal Stem Cell Survival in Ischemic Heart With a Hypoxia-Regulated Heme Oxygenase-1 Vector
Yao Liang Tang, MD, PhD*, Yi Tang, MD, PhD§, Y. Clare Zhang, PhD{dagger},{ddagger}, Keping Qian, PhD{dagger},{ddagger}, Leping Shen, MS{dagger},{ddagger} and M. Ian Phillips, PhD, DSc*,*
* Department of Physiology and Biophysics, University of South Florida, St. Petersburg, Florida
{dagger} Department of Pediatrics, College of Medicine, University of South Florida, St. Petersburg, Florida
{ddagger} All Children’s Hospital Research Institute, University of South Florida, St. Petersburg, Florida
§ Department of Surgery, University of Stanford, Stanford, California
OBJECTIVES: 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 106 of male MSCHO-1, MSCLacZ, 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 MSCHO-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 MSCLacZ group. At seven days after implantation, the survival MSCHO-1 was five-fold greater than the MSCLacZ group; MSCHO-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.
J Am Coll Cardiol, 2005; 46:1339-1350, doi:10.1016/j.jacc.2005.05.079