Abstract 12290: Exosomal miR-223 Contributes to Mesenchymal Stem Cell-Elicited Cardio-protection in Polymicrobial Sepsis
Background: Mesenchymal stem cells (MSCs) have been shown to elicit cardioprotective effects in polymicrobial sepsis induced by cecal ligation and puncture (CLP). However, the underlying mechanisms remain obscure. While recent studies have indicated that miR-223 is highly enriched in MSC-derived exosomes, whether exosomal miR-223 contributes to MSC-mediated cardioprotection in sepsis is unknown.
Methods and Results: MSCs harvested from the bone marrow of female pre-miR-223 knockout (KO) and wild-type (WT) mice were injected into male WT mice via the tail vein 1 h after CLP. We observed that the mortality of mice at 32h post-CLP was significantly reduced in WT- MSC-injected mice, but not in KO-MSC-treated groups, compared with controls. CLP-triggered cardiac dysfunction, apoptosis and inflammatory response were also attenuated in mice treated with WT-MSCs, but not miR-223 KO-MSCs. Furthermore, in vitro study showed that WT-MSCs could release miR-223-enrinched exosomes (WT-exosomes) that were taken up by macrophages and cardiomyocytes, leading to reduced production of pro-inflammatory factors (TNF-α, IL-1β, and IL-6) from macrophages and cardiomyocyte death upon LPS insults. By contrast, miR-223-KO-exosomes stimulated macrophage to release these cytokines and increased cardiomyocyte death upon LPS challenge. In vivo study showed that injection of KO-exosomes into the tail vein of mice at 1h post-CLP significantly increased: 1) serum levels of TNF-α, IL-1β, and IL-6; 2) cardiac dysfunction; and 3) animal mortality. Conversely, treatment of mice with WT-exosomes displayed the opposite effects. Mechanistically, we identified that miR-223-KO exosomes contained higher levels of Sema3A and Stat3, two known targets of miR-223 (5p & 3p), than WT-exosomes. Accordingly, these exosomal proteins were able to be transferred to macrophages and cardiomyocytes, leading to increased inflammation and cell death. By contrast, WT-exosomes encased higher levels of miR-223, which could be delivered to macrophages and cardiomyocytes, resulting in down-regulation of Sema3A and Stat3.
Conclusions: These data for the first time indicate that exosomal miR-223 plays an essential role for MSC-induced cardioprotection in sepsis.
Author Disclosures: X. Wang: None. W. Huang: None. Y. Wang: None. G. Fan: None.
- © 2015 by American Heart Association, Inc.