Author + information
- Received December 27, 2004
- Revision received April 9, 2005
- Accepted May 17, 2005
- Published online October 4, 2005.
- 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⁎,⁎ ()
- ↵⁎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
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 × 106of 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-1group 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 MSCLacZgroup. At seven days after implantation, the survival MSCHO-1was five-fold greater than the MSCLacZgroup; MSCHO-1also 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.
Dr. Yao Liang Tang is recipient of postdoctoral fellowship from American Heart Association (0325378B). Dr. Phillips is supported by grants from the National institutes of Health HL 77602, MERIT HL27339. Dr. Yi Tang is recipient of predoctoral fellowship from American Heart Association (0110140B).
- Received December 27, 2004.
- Revision received April 9, 2005.
- Accepted May 17, 2005.
- American College of Cardiology Foundation