Abstract 3570: Cardiac Repair With Transendocardial Injection of Allogeneic Mesenchymal Precursor Cells for Nonischemic Cardiomyopathy
Background: Prospectively isolated bone marrow (BM) mesenchymal precursor cells (MPC) have shown capacity to mediate cardiovascular repair in myocardial ischemia. However, their efficacy in nonischemic cardiomyopathy (NICM) remains undetermined. We evaluated the efficacy of intramyocardial MPC transplantation in a preclinical model of NICM.
Methods: MPC were prepared from ovine BM by immunoselection using an antibody to tissue non-specific alkaline phosphatase (STRO-3). Sixteen sheep with doxorubicin-induced NICM were randomized to either intramyocardial therapy with allogeneic MPC (5×106 cells ×20 injections) or placebo, delivered multi-segmentally to the left ventricle (LV) under electromechanical, NOGA® XP guidance. Follow-up was for 8 weeks with end-points assessed by cardiac MRI, echocardiography and histology.
Results: Transendocardial injections were well-tolerated and were similarly distributed in both groups. Cell transplantation was associated with better animal survival during follow-up (1 death v 3 deaths placebo). Ejection fraction was stabilized after MPC (37.0±2.7% pre, 36.9±2.2% post, P=N.S.) but declined substantially after placebo (38.1±5.5% pre, 31.3±4.7% post, P<0.05). Similar results were noted for fractional shortening (ΔFS +2.4±2.6% MPC v −4.4±1.3% placebo, P<0.05). MPC therapy was also associated with less LV fibrosis (5.6±0.4% v 7.1±0.3%, P<0.05), more proliferating Ki67+ cardiomyocytes and greater myocardial vascular density. These benefits occurred despite a lack of sustained myocardial engraftment of MPC one month after transplantation. In vitro assays confirmed the paracrine capacity of STRO-3-selected MPC. MPC conditioned medium contained cardiovascular relevant mediators (CXCL12, HGF, VEGF, MCP-1, IL-6) and augmented endothelial tube formation (by 24.6±6.0% v control, P<0.01), cardiac cell proliferation and migration, and reduced cardiac cell death during exposure to doxorubicin (by 31.3±4.0%, P<0.01).
Conclusion: In NICM, multi-segmental, intramyocardial delivery of cell therapy can be safely achieved using NOGA® XP. The pleiotropic properties of immunoselected MPC include anti-fibrotic, pro-mitogenic and pro-vasculogenic effects that confer therapeutic benefit to NICM.