Exosomal miR-223 Contributes to Mesenchymal Stem Cell-Elicited Cardioprotection in Polymicrobial Sepsis.
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.
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Xiaohong
X
Wang
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Haitao
H
Gu
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Shanxi Medical University, Taiyuan, China.
Dongze
D
Qin
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Shanxi University of Traditional Chinese Medicine, Taiyuan, China.
Liwang
L
Yang
Department of Pathology and Laboratory Medicine , University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Wei
W
Huang
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Kobina
K
Essandoh
Department of Pathology and Laboratory Medicine , University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Yigang
Y
Wang
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Charles C
CC
Caldwell
Critical Illness Research, Lawson Health Research Institute, Ontario, Canada N6A 4G5.
Tianqing
T
Peng
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Basilia
B
Zingarelli
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Guo-Chang
GC
Fan
D000818:Animals; D016923:Cell Death; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D055354:Exosomes / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006331:Heart Diseases / Q000209:etiology* / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D040121:Semaphorin-3A / Q000378:metabolism; D018805:Sepsis / Q000150:complications* / Q000382:microbiology* / Q000401:mortality
D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C544877:MIRN223 microRNA, mouse; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; D040121:Semaphorin-3A