Abstract 154: Allogeneic Cardiosphere-derived Cells From an Aged Donor Elicit Long-term Improvements in Left Ventricular Function and Myocyte Proliferation in a Mini-swine Model of Chronic Myocardial Ischemia
Objective: Virtually all large animal studies of cell-based therapy have employed young donor-recipient pairs. Since aging may impact the reparative ability of allogeneic cardiosphere-derived cells (CDCs), we tested whether CDCs from an aged donor promote functional repair of ischemic myocardium using a mini-swine model that enabled serial assessment of left ventricular (LV) function over an extended follow-up period.
Methods: Immunosuppressed mini-swine (cyclosporine 100 mg/day) with a chronic (4-months) LAD stenosis were untreated (n=8) or received 20 million allogeneic aged CDCs (n=10). Cells were cultivated from a 9-year old mini-pig and infused into the 3 major coronary arteries under continuous flow (1 million cells/min). LV function was assessed by echocardiography at baseline and over a 3-month follow-up period, at which time histological assessment of myocyte morphometry, proliferation (Ki67), and cell retention (Y-FISH) was performed.
Results: Wall thickening (WT) of the ischemic LAD region was impaired at baseline (LAD: 42.7 ± 2.1% vs. Remote: 81.4 ± 4.8%, p<0.01) and not different between treatment groups. One month later, LAD WT improved in aged CDC-treated animals (from 41.0 ± 3.1 to 53.0 ± 1.7%, p=0.01) but remained depressed in untreated animals (from 45.1 ± 2.8% to 44.9 ± 2.6%, p=0.97). Extended follow-up revealed that LAD WT continued to improve, reaching 60.2 ± 1.6% (p=0.01) 3-months after CDC treatment. Histological analyses demonstrated morphometric changes consistent with myocyte regeneration, including an increase in myocyte nuclear density (1231 ± 34 vs. 1094 ± 34 nuclei/mm2, p=0.02) and reduction in myocyte diameter (13.9 ± 0.2 vs. 14.5 ± 0.3 μm, p=0.05). Increases in Ki67+ myocytes (468 ± 92 vs. 199 ± 32 nuclei/106 myocyte nuclei, p=0.02) and rare Y+ cells in sex-mismatched recipients (0.5 ± 0.2 cells/cm2) supported endogenous myocyte proliferation as the primary source of new myocytes.
Conclusion: CDCs from an aged donor retain their reparative capacity to promote functional improvement and increase myocyte number following global intracoronary infusion. The progressive improvement in LV function 3-months after treatment with ongoing myocyte proliferation supports a long-lasting benefit after a single infusion.
Author Disclosures: B.R. Weil: None. G. Suzuki: None. M.M. Leiker: None. A. Goelz: None. J.M. Canty: None.
This research has received full or partial funding support from the American Heart Association, Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).
- © 2015 by American Heart Association, Inc.