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 , ,
Keping Qian, PhD,,
Leping Shen, MS, and
M. Ian Phillips, PhD, DSc*,*
* Department of Physiology and Biophysics, University of South Florida, St. Petersburg, Florida
Department of Pediatrics, College of Medicine, University of South Florida, St. Petersburg, Florida
All Children’s Hospital Research Institute, University of South Florida, St. Petersburg, Florida
Department of Surgery, University of Stanford, Stanford, California
Manuscript received December 27, 2004;
revised manuscript received April 9, 2005,
accepted May 17, 2005.
* Reprint requests and correspondence: Dr. M. Ian Phillips, Vice President for Research and Professor of Medicine, 4202 East Fowler Avenue, ADM200, Tampa, Florida 33620-5950 (Email: iphillips{at}research.usf.edu).
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.
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Abbreviations and Acronyms
| | cTNT = cardiac troponin T | | DAPI = 4',6-diamidino-2'-phenylindole | | FITC = fluorescein isothiocyanate | | HO-1 = heme oxygenase-1 | | IL = interleukin | | LV = left ventricular | | MI = myocardial infarction | | MSC = mesenchymal stem cell | | OST = oxygen-sensitive toggle | | PCR = polymerase chain reaction | | TRITC = tetramethyl rhodamine isothiocyanate | | TUNEL = terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling |
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