Abstract 15111: Ctrp9 Enhances the Proliferation, Survival, and Paracrine Effect of Engrafted Adipose-Derived Mesenchymal Stem Cells (adsc) in Post-mi Mouse Heart
Objective: The poor survival of engrafted stem cells in the ischemic environment limits their therapeutic efficacy for myocardial infarction (MI) treatment. Previously, we demonstrated that administration of a novel adipokine/cardiokine, C1q/tumor necrosis factor-related protein-9 (CTRP9), reduced post-MI remodeling. The current study investigated whether CTRP9 facilitates post-MI heart repair by engrafted adipose-derived mesenchymal stem cells (ADSC).
Methods and Results: C57BL/6J mouse ADSC were isolated and transfected with adenovirus harboring enhanced green fluorescent protein (EGFP). Mice were randomized to the following groups: 1) Sham MI; 2) MI+PBS; 3) MI+CTRP9 (0.25 μg/g/d via peritoneal implant osmotic pumps for 2 weeks); 4) MI+ADSC (1х105 passage 3 cells directly injected into peri-infarct area immediately post-MI); or 5) MI+ADSC+CTRP9. Echocardiography assessed cardiac function 1, 2, 3, and 4 weeks after surgery. Histological analysis (EGFP, CD31, and masson-trichrome staining) determined ADSC survival, capillary density, and fibrosis. CTRP9 treatment atop ADSC implantation significantly improved LVEF (30.5±3.6% in MI+ADSC+CTRP9 group vs. 22.8±2.7% in MI+ADSC group; P < 0.01) 4 weeks after MI. CTRP9 treatment enhanced engrafted ADSC survival 1 week after MI. Moreover, CTRP9+ADSC significantly increased capillary density and reduced fibrosis 4 weeks after MI. In vitro study further demonstrated that CTRP9 significantly increased ADSC proliferative rate (~1.4 fold), decreased hydrogen peroxide-induced cell death (~25%), and enhanced paracrine effect (angiopoietin 1 and VEGFA, ~2-3 fold) in vitro (P all<0.01). CTRP9 increased phosphorylation of Akt and ERK1/2, but not AMPK. Surprisingly, AdipoR1 knockout failed to block CTRP9’s effects upon ADSC proliferation, H2O2-induced cell death, and paracrine function.
Conclusion: We demonstrate for the first time that CTRP9 enhances ADSC therapeutic MI efficacy in an AdipoR1-independent fashion, suggesting the beneficial role of CTRP9 may be linked to its effects upon stem cell proliferation, survival, and paracrine function.
Author Disclosures: W. Yan: None. Y. Guo: None. G. Lu: None. Y. Chen: None. W. Lau: None. L. Tao: None. E. Gao: None. W. Koch: None. Y. Wang: None. X. Ma: None.
- © 2016 by American Heart Association, Inc.