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

Wang X, Gu H, Qin D, Yang L, Huang W, Essandoh K, Wang Y, Caldwell CC, Peng T, Zingarelli B, Fan GC - Sci Rep (2015)

Bottom Line: However, WT-MSCs were able to provide protection which was associated with exosome release.Conversely, WT-MSC-derived-exosomes displayed protective effects.By contrast, WT-exosomes encased higher levels of miR-223, which could be delivered to cardiomyocytes, resulting in down-regulation of Sema3A and Stat3.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 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.

No MeSH data available.


Related in: MedlinePlus

A work model elucidating that miR-223 contributes to MSC-elicited protective effects against sepsis through the exosome-mediated transfer of miR-223 to other types of cells (i.e. macrophages and cardiomyocytes), leading to attenuation of inflammatory response and inhibition of cell death in recipient cells.
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f8: A work model elucidating that miR-223 contributes to MSC-elicited protective effects against sepsis through the exosome-mediated transfer of miR-223 to other types of cells (i.e. macrophages and cardiomyocytes), leading to attenuation of inflammatory response and inhibition of cell death in recipient cells.

Mentions: In this study, we center on elucidating the mechanisms underlying MSC-mediated cardio-protection in sepsis. Major findings of the present study include: 1) miR-223- MSCs did not improve myocardial function and survival rate when they were injected into septic mice; 2) blockade of exosome generation in vitro with GW4869 impaired MSC-induced suppression of inflammation in macrophages and offset MSC-elicited protective effects in cardiomyocytes upon LPS challenge; 3) miR-223-absent exosomes derived from KO-MSCs aggravated sepsis-induced heart failure, inflammatory response, and mortality through the exosomal transfer of Sema3A and Stat3 to the myocardium; and 4) miR-223-present exosomes derived from WT-MSCs attenuated sepsis-trigged myocardial depression through the exosomal transfer of miR-223 to recipient cells and consequently, down-regulated the expression of Sema3A and Stat3, leading to the reduction of inflammatory response and cell death (Fig. 8). Our findings for the first time suggest that MSC-induced protective effects on sepsis may be largely dependent on exosomal miR-223.


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

Wang X, Gu H, Qin D, Yang L, Huang W, Essandoh K, Wang Y, Caldwell CC, Peng T, Zingarelli B, Fan GC - Sci Rep (2015)

A work model elucidating that miR-223 contributes to MSC-elicited protective effects against sepsis through the exosome-mediated transfer of miR-223 to other types of cells (i.e. macrophages and cardiomyocytes), leading to attenuation of inflammatory response and inhibition of cell death in recipient cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562230&req=5

f8: A work model elucidating that miR-223 contributes to MSC-elicited protective effects against sepsis through the exosome-mediated transfer of miR-223 to other types of cells (i.e. macrophages and cardiomyocytes), leading to attenuation of inflammatory response and inhibition of cell death in recipient cells.
Mentions: In this study, we center on elucidating the mechanisms underlying MSC-mediated cardio-protection in sepsis. Major findings of the present study include: 1) miR-223- MSCs did not improve myocardial function and survival rate when they were injected into septic mice; 2) blockade of exosome generation in vitro with GW4869 impaired MSC-induced suppression of inflammation in macrophages and offset MSC-elicited protective effects in cardiomyocytes upon LPS challenge; 3) miR-223-absent exosomes derived from KO-MSCs aggravated sepsis-induced heart failure, inflammatory response, and mortality through the exosomal transfer of Sema3A and Stat3 to the myocardium; and 4) miR-223-present exosomes derived from WT-MSCs attenuated sepsis-trigged myocardial depression through the exosomal transfer of miR-223 to recipient cells and consequently, down-regulated the expression of Sema3A and Stat3, leading to the reduction of inflammatory response and cell death (Fig. 8). Our findings for the first time suggest that MSC-induced protective effects on sepsis may be largely dependent on exosomal miR-223.

Bottom Line: However, WT-MSCs were able to provide protection which was associated with exosome release.Conversely, WT-MSC-derived-exosomes displayed protective effects.By contrast, WT-exosomes encased higher levels of miR-223, which could be delivered to cardiomyocytes, resulting in down-regulation of Sema3A and Stat3.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 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.

No MeSH data available.


Related in: MedlinePlus