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Sci Rep. 2015 Sep 8;5:13721. doi: 10.1038/srep13721.

Exosomal miR-223 Contributes to Mesenchymal Stem Cell-Elicited Cardioprotection in Polymicrobial Sepsis.

Author information

1
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
2
Shanxi Medical University, Taiyuan, China.
3
Shanxi University of Traditional Chinese Medicine, Taiyuan, China.
4
Department of Pathology and Laboratory Medicine , University of Cincinnati College of Medicine, Cincinnati, OH, USA.
5
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
6
Critical Illness Research, Lawson Health Research Institute, Ontario, Canada N6A 4G5.
7
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Abstract

Mesenchymal stem cells (MSCs) have been shown to elicit cardio-protective effects in sepsis. However, the underlying mechanism remains obscure. While recent studies have indicated that miR-223 is highly enriched in MSC-derived exosomes, whether exosomal miR-223 contributes to MSC-mediated cardio-protection in sepsis is unknown. In this study, loss-of-function approach was utilized, and sepsis was induced by cecal ligation and puncture (CLP). We observed that injection of miR-223-KO MSCs at 1 h post-CLP did not confer protection against CLP-triggered cardiac dysfunction, apoptosis and inflammatory response. However, WT-MSCs were able to provide protection which was associated with exosome release. Next, treatment of CLP mice with exosomes released from miR-223-KO MSCs significantly exaggerated sepsis-induced injury. Conversely, WT-MSC-derived-exosomes displayed protective 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 transferred to cardiomyocytes, leading to increased inflammation and cell death. By contrast, WT-exosomes encased higher levels of miR-223, which could be delivered to cardiomyocytes, resulting in down-regulation of Sema3A and Stat3. These data for the first time indicate that exosomal miR-223 plays an essential role for MSC-induced cardio-protection in sepsis.

PMID:
26348153
PMCID:
PMC4562230
DOI:
10.1038/srep13721
[Indexed for MEDLINE]
Free PMC Article

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