Abstract 14697: Microrna-Containing Exosomes from Cardiosphere-Derived Cells Stimulate Cardiomyocyte Proliferation and Angiogenesis in vitro, and Improve Functional Recovery after Myocardial Infarction in Mice
Background: Exosomes are nano-sized bilayer vesicles that are secreted by most cell types. Exosomes are rich in microRNAs (mirs) which may function in a paracrine fashion. Cardiosphere-derived cells (CDCs) have been shown to regenerate heart after myocardial infarction (MI) in animal models and in the CADUCEUS clinical trial. However, most of the regenerated muscle is of innate origin, which suggests that CDCs function mainly through indirect pathways.
Methods and Results: In vitro and in vivo, we compared three treatment groups: vehicle only (control), CDC-derived exosomes and normal human dermal fibroblast (NHDF)-derived exosomes. Neonatal rat cardiomyocytes incubated with CDC exosomes expressed higher levels of Ki67 (CDC: 42.7 ± 0.04%, NHDF: 22.5 ± 0.04%, control: 9.1% ± 0.03, n=4, p<0.001) and lower expression of tunel compared to NHDF exosomes or control (CDC: 25.2 ± 0.04%, NHDF: 45.1 ± 0.05, control: 41.4 ± 0.05%, n=4, p<0.01). CDC exosomes also stimulated tube formation in HUVEC cells compared to NHDF exosomes or control (CDC: 9393 ± 689; NHDF: 2813 ± 494.5; control: 1097 ± 116.1, n=3, p<0.05). SCID mice injected with exosomes from CDCs during acute MI showed higher LVEF at two weeks (CDC: 40.8 ± 2.33 NHDF: 32.34 ± 2.0, control: 31.31 ± 3.2, n=6, p<0.05) and four weeks (CDC: 44.03 ± 1.5 NHDF: 31.8 ± 1.7, control: 31.5 ± 2.7, n=6, p<0.05) post MI (Fig: A), as well as increased regeneration of the infarcted myocardium. CDC exosome-treated animals also showed lower expression of pro-inflammatory markers in heart tissue at 4 weeks post MI including GCSF, fractalkine and IL-12, and MIP-1g (Fig: B). Mir microarray analysis identified mir-146a, mir 22, mir 24, and mir 210 among the most highly-upregulated mirs in CDC-exosomes compared to NHDF (262, 59, 50, and 30 fold respectively).
Conclusions: Mir-containing exosomes secreted by CDCs exhibit multiple beneficial effects on injured myocardium, suggesting that exosomes may mediate some of the therapeutic effects of CDCs.
- © 2012 by American Heart Association, Inc.