Abstract 18016: Cell and Hydrogel-based Therapies Employing Cathelicidin Related Antimicrobial Peptide (CRAMP) Attenuate Cardiac Dysfunction in a Mouse Model of Myocardial Infarction: Potential Therapeutic Targets in Ischemic Heart Disease

Abstract

Introduction: Limited stem cell retention following intracoronary administration has reduced the clinical efficacy of this novel therapy. Cathelicidins related antimicrobial proteins (CRAMPs) have been shown to prime bone marrow Derived mononuclear Cells (BMMNC) migration towards low gradients of SDF-1 suggesting a potential role in BMMNC retention. Here, we assessed the therapeutic efficacy of CRAMP in the context of BMMNC recruitment and retention via intracardiac delivery of CRAMP-treated BMMNCs or CRAMP-packed hydrogels (HG) post-myocardial infarction (MI). Methods and Results: During the in vivo cell studies, mice were randomized into 3 groups: MI followed by injection of PBS, BMMNCs alone, and BMMNCs incubated with CRAMP. During the in vivo HG studies, BM GFP chimera mice were randomized into 4 groups: MI followed by injection of HG alone, HG + SDF-1, HG + SDF-1 + CRAMP, HG + CRAMP. Changes in infarct size and cardiac function between 5 days and 5 weeks after MI were assessed using cardiac MRI (CMR) and echocardiography respectively. Treatment of BMMNCs with CRAMP enhanced their migration towards low, yet physiological, levels of SDF-1 in vitro (Fig 1A). In vivo, BMMNC+CRAMP therapy was associated with significant increase in capillary density as compared to the BMMNC-alone and control groups (Fig 1B). Moreover, BMMNC+CRAMP administration led to improvement in cardiac function and reduction in infarct size as compared to other groups (Fig 1C-D). Similar to the BMMNCs+CRAMP cell therapy, HG + SDF-1 + CRAMP administration post-MI led to improvement of cardiac function and reduction in infarct size compared with other groups (Fig 1E-F). Conclusion: Cathelicidins enhance BMMNC retention and recruitment after intramyocardial administration post-MI resulting in improvements in heart physiology and recovery. Therapies employing these strategies may represent an attractive method for improving outcomes of regenerative therapies in human studies.