Abstract 2094: Hemeoxygenase-1 Gene Modification Enhances the Regenerative Efficacy of CD34+Cell-Therapy After Myocardial Infarction
Hemeoxygenase-1 (HO-1), the rate-limiting enzyme in heme metabolism, is known to exert cytoprotection in various pathologic states via its anti-oxidative, anti-apoptotic, anti-inflammatory properties. HO-1 has recently been linked to vasculogenesis and progenitor biology. Since the regenerative potential of cell-therapy is limited by low survival and retention of transplanted cells in the ischemic target zone, we hypothesized that HO-1 modification could enhance the regenerative efficacy of CD34+cells in ischemic tissue repair. Human CD34+cells enriched (Isolex 300i, Baxter) from G-CSF mobilized peripheral blood MNC were transduced by HO-1/GFP or GFP adenovirus (relative HO-1/18s RNA expression: 60-fold increase; protein expression: 15-fold increase). Forty-eight hrs later, cells were FACS sorted for GFP. Following recovery overnight a subtherapeutic dose (105 cells/kg) of GFP+ (CD34) or HO-1+/GFP+CD34+ cells (HO-1/CD34) or PBS (2× 15 μl) (PBS) was locally injected into the border zone after complete ligation of the left coronary artery in 8-week-old, male nude mice. In hearts harvested at day 28, infarct size was reduced in mice treated with HO-1 modified vs. unmodified CD34 cells (Masson-trichrome: CD34 42.6±0.9%, HO-1/CD34 35.8±1.5%, n=7– 8/group, P<0.01). In the infarct border zone histologic analysis revealed more lectin+ capillaries (CD34 79±7/hpf, HO-1/CD34 99±4/hpf, n=7– 8/group, P<0.05), while lectin+/α smooth-muscle actin+ structures indicative for resistance vessels, remained equally distributed (CD34 8±1/hpf, HO-1/CD34 5±1/hpf, n=7– 8/group, P=ns). Echocardiography 28 days after MI revealed better LV ejection fraction in mice treated with HO-1 over-expressing CD34+ cells (CD34 36.7±5.1%, HO-1/CD34 44.3±4.5%; n=7– 8/group, P<0.05). Finally, findings are associated with a better survival of HO-1/CD34 treated mice (MI 20±4; HO-1/CD34 27±1; CD34 21±4 days).
Conclusion: adenovirally mediated HO-1 gene modification enhances the efficacy of CD34+ cell-based therapies in ischemic tissue repair. Ongoing studies are addressing the underlying mechanism(s).
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).