Cathelicidin Related Antimicrobial Peptide (CRAMP) Enhances Bone Marrow Cell Retention and Attenuates Cardiac Dysfunction in a Mouse Model of Myocardial Infarction
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Acute myocardial infarction (MI) and the ensuing ischemic heart disease are approaching epidemic state. Unfortunately, no definitive therapies are available and human regenerative therapies have conflicting results. Limited stem cell retention following intracoronary administration has reduced the clinical efficacy of this novel therapy. Cathelicidin related antimicrobial peptides (CRAMPs) enhance chemotactic responsiveness of BMSPCs to low SDF-1 gradients, suggesting a potential role in BMSPCs engraftment. Here, we assessed the therapeutic efficacy of CRAMPs in the context of BMSPCs recruitment and retention via intracardiac delivery of CRAMP-treated BMSPCs or CRAMP-releasing hydrogels (HG) post-AMI.
For cell transplantation experiments, mice were randomized into 3 groups: MI followed by injection of PBS, BMMNCs alone, and BMMNCs pre-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 + CRAMP, HG + SDF-1 + CRAMP. Changes in cardiac function at 5 weeks after MI were assessed using echocardiography. Angiogenesis was assessed using isolectin staining for capillary density.
Mice treated with BMMNCs pre-incubated with CRAMP had smaller scars, enhanced cardiac recovery and less adverse remodeling. Histologically, this group had higher capillary density. Similarly, sustained CRAMP release from hydrogels enhanced the therapeutic effect of SDF-1, leading to enhanced functional recovery, smaller scar size and higher capillary density.
Cathelicidins enhance BMMNC retention and recruitment after intramyocardial administration post-AMI 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.
KeywordsBone marrow derived mononuclear cells (BMMNCs) Cathelicidin related antimicrobial peptide (CRAMP) LL-37 Myocardial infarction Regeneration Stem cells homing
Acute Myocardial Infarction
Bone Marrow mononuclear cells
Cathelicidin-related antimicrobial peptides
End Systolic Volume
Left Anterior Descending Artery
Dr. Abdel-Latif is supported by the University of Kentucky Clinical and Translational Science Pilot Award (UL1TR000117), the UK COBRE Early Career Program (P20 GM103527) and the NIH Grant R56 HL124266. Dr. Nagareddy is supported by the NIH Pathway to Independence Award (1K99HL122505-01). Dr. Ye is supported by the T32 grant (HL091812). Dr. Ratajczak is supported by NIH grants 2R01 DK074720 and R01HL112788. Christopher B. Rodell is supported by an American Heart Association Predoctoral Fellowship. Jason A. Burdick is supported by an American Heart Association Established Investigator Award.
Yuri Klyachkin: conception and design, data analysis and interpretation and manuscript writing. Amr Idris: conception and design, data analysis and interpretation and manuscript writing. Christopher B. Rodell: conception and design, synthesis and preparation of hydrogels, data analysis and interpretation and manuscript writing. Himi Tripathi: collection and/or assembly of data and data analysis and interpretation. Shaojing Ye: collection and/or assembly of data and data analysis and interpretation. Prabakara Nagareddy: collection and/or assembly of data and data analysis and interpretation. Ahmed Asfour: collection and/or assembly of data. Erhe Gao: collection and/or assembly of data. Rahul Annabathula: collection and/or assembly of data. Jason A Burdick: conception and design, data interpretation and manuscript writing. Mariusz Ratajczak: conception and design, data analysis and interpretation and manuscript writing. Ahmed Abdel-Latif: conception and design, data analysis and interpretation, provision of study material or patients, financial support and manuscript writing.
Compliance with Ethical Standards
Conflict of Interest
- 7.McQuibban, G. A., Gong, J. H., Wong, J. P., Wallace, J. L., Clark-Lewis, I., & Overall, C. M. (2002). Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood, 100, 1160–1167.PubMedGoogle Scholar
- 8.Purcell, B. P., Elser, J. A., Mu, A., Margulies, K. B., & Burdick, J. A. (2012). Synergistic effects of SDF-1alpha chemokine and hyaluronic acid release from degradable hydrogels on directing bone marrow derived cell homing to the myocardium. Biomaterials, 33, 7849–7857.CrossRefPubMedPubMedCentralGoogle Scholar
- 9.MacArthur Jr., J. W., Purcell, B. P., Shudo, Y., et al. (2013). Sustained release of engineered stromal cell-derived factor 1-alpha from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction. Circulation, 128, S79–S86.CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Wu, W., Kim, C. H., Liu, R., et al. (2012). The bone marrow-expressed antimicrobial cationic peptide LL-37 enhances the responsiveness of hematopoietic stem progenitor cells to an SDF-1 gradient and accelerates their engraftment after transplantation. Leukemia, 26, 736–745.CrossRefPubMedGoogle Scholar
- 11.Karapetyan, A. V., Klyachkin, Y. M., Selim, S. M., et al. (2013). Bioactive lipids and cationic antimicrobial peptides as new potential regulators for trafficking of bone marrow derived stem cell in patients with acute myocardial infarction. Stem Cells and Development, 22, 1645–1656.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Abbott, J. D., Huang, Y., Liu, D., Hickey, R., Krause, D. S., & Giordano, F. J. (2004). Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation, 110, 3300–3305.CrossRefPubMedGoogle Scholar
- 23.Karapetyan, A. V., Klyachkin, Y. M., Selim, S., et al. (2013). Bioactive lipids and cationic antimicrobial peptides as new potential regulators for trafficking of bone marrow-derived stem cells in patients with acute myocardial infarction. Stem Cells and Development, 22, 1645–1656.CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Anker, S. D., Coats, A. J., Cristian, G., et al. (2015). A prospective comparison of alginate-hydrogel with standard medical therapy to determine impact on functional capacity and clinical outcomes in patients with advanced heart failure (AUGMENT-HF trial). European Heart Journal, 36, 2297–2309.CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Frey, N., Linke, A., Suselbeck, T., et al. (2014). Intracoronary delivery of injectable bioabsorbable scaffold (IK-5001) to treat left ventricular remodeling after ST-elevation myocardial infarction: A first-in-man study. Circulation. Cardiovascular Interventions, 7, 806–812.CrossRefPubMedGoogle Scholar
- 30.Lee, R. J., Hinson, A., Bauernschmitt, R., et al. (2015). The feasibility and safety of Algisyl-LVR as a method of left ventricular augmentation in patients with dilated cardiomyopathy: Initial first in man clinical results. International Journal of Cardiology, 199, 18–24.CrossRefPubMedGoogle Scholar