Abstract 15884: Cardiosphere-Derived Cells Confer Acute Cardioprotection Following Ischemia-Reperfusion Injury in Rats: Role of Macrophage Polarization
Introduction: Cardiosphere-derived cells (CDCs) confer both cardioprotection and regeneration in acute myocardial infarction (MI). However, only long-term (>3 wks) post-MI endpoints have been studied, making it impossible to investigate the cardioprotective effects in isolation. Macrophages (MF) concentrate within the heart following ischemic injury as part of the inflammatory response to injury. Here we test the hypothesis that CDCs are cardioprotective by modifying MF within the myocardium post-MI.
Methods & Results: Wistar-Kyoto rats (aged 8-12 wks) underwent 45 min of ischemia followed by 20 min of reperfusion, then intracoronary (i.c.) infusion of either saline or CDCs (5x105). The use of a 48 hr endpoint enabled the selective study of cardioprotection. CDC-treated animals had preserved ejection fraction (59.2% vs. 47.4%; p<0.001) and reduced infarct size (TTC; 6.3% vs. 13.6%; p<0.01). The finding that CDC-treated hearts contained fewer CD68+ MF (p<0.05) suggested a mechanistic role for MF, a conjecture which we tested in detail. MF isolated from CDC-treated hearts secreted lower amounts of proinflammatory cytokines (Nos2, Tnf, Il1b; p<0.05). Systemic depletion of MF with clodronate liposomes attenuated the benefits of CDC therapy post-MI (p<0.05). In vitro, MF conditioned by transwell exposure to CDCs (MCDC) exhibited distinct gene profiles relative to proinflammatory M1 or “healing” M2 polarization states (MCDC: Il10; M1: Nos2; M2: Arg1, Pparg). Adoptive transfer of selective MF populations into the heart (i.c.; 20 min post-reflow) revealed that MCDC, but not M1 or M2 MF, could recapitulate the reduction in infarct size (MCDC: 4.5%; M1: 14.0%; M2: 10.8%; p<0.05). In vitro co-culture shows that MCDC selectively reduce cardiomyocyte apoptosis following oxidant stress (MCDC: 9.9%; M1: 39.4%; M2: 37.4%; p<0.001).
Conclusions: CDCs are cardioprotective when administered 20 min after reflow; the timing distinguishes this form of cardioprotection from preconditioning or ischemic postconditioning. Various lines of evidence indicate that CDCs work by polarizing MF toward a cardioprotective phenotype. The findings motivate further translational development of the adjunctive use of CDCs post-MI to limit infarct size.
Author Disclosures: G. de Couto: None. H. Kanazawa: None. E. Tseliou: None. L. Marbán: Ownership Interest; Significant; Capricor Inc. E. Marbán: Ownership Interest; Significant; Capricor Inc..
- © 2014 by American Heart Association, Inc.