Abstract 15149: Exosome-Mediated Anti-Aging Effects of Cardiosphere-Derived Cells
Introduction: Cell senescence underlies and/or exacerbates age-related cardiovascular pathologies. Cardiosphere -derived cell (CDC) therapy has demonstrated several favorable effects on heart structure and function in humans and in preclinical models; however, the effects of CDCs on aging have not been evaluated.
Objectives: 1) To determine if CDCs and exosomes secreted by CDCs (CDC-EXO) affect heart cell senescence. 2) To evaluate possible causes and consequences of the CDC-mediated rejuvenation of heart cells.
Methods: Heart biopsies in primary culture release explant-derived cells (EDC), which include cardiac progenitor and stromal cells. EDCs from old human donors were co-cultured with CDC or CDC-EXO from young (< 2-year-old) human donors. 24-months old rat cardiomyocytes were isolated by Langendorff procedure and treated with young CDC-XO.
Results: After CDC or CDC-EXO exposure, the number of SA-GAL+ senescent cells decreased among old EDCs relative to those treated with serum-free-media as a control (54.2 vs 38.2 cells/field, p=0.01). Telomerase activity increased up to 6.4 fold with CDC-EXO (p<0.001) and 4.2 fold with CDC (p=0.02). This effect was abrogated by pretreatment of CDCs with GW4869, a blocker of exosome production. Mean telomere length was higher in CDC-treated old EDCs (34.1 vs 28.1 i.o.d. in control group, p<0.001). CDC-EXO-treated old EDCs showed a higher proliferation rate (230 vs 179 cells/field, p=0.03), lower apoptosis (1.6% vs 3.4% TUNEL+ cells, p=0.02), and higher self-assembly potential as indexed by the number and size of the EDC-produced cardiospheres (327 vs 115 spheres/ml and 15 fold increase in spheres > 100 um in diameter, p=0.04 in both cases). Analogous benefits were observed when old cardiomyocytes were exposed to CDC-EXO in primary culture (e.g., 2.5-fold higher survival of adult cardiomyocytes after 120 hr, p<0.01).
Conclusions: The findings reveal a novel exosome-mediated mechanism of cellular rejuvenation. CDC and CDC-EXO increase telomerase activity, lengthen telomeres, decrease cell senescence in old heart cells, increasing their proliferative capacity and reducing cell death. The data raise the intriguing possibility that CDCs and CDC-EXO may benefit age-related cardiac dysfunction.
Author Disclosures: L. Grigorian: None. S. Fereydooni: None. R. Middleton: None. W. Liu: None. M. Kreke: None. J. Valle: None. E. Marbán: Ownership Interest; Modest; Capricor. Consultant/Advisory Board; Modest; Capricor.
- © 2016 by American Heart Association, Inc.