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Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22.

Feng Y, Huang W, Wani M, Yu X, Ashraf M - PLoS ONE (2014)

Bottom Line: Furthermore, the anti-apoptotic effect of miR-22 was mediated by direct targeting of methyl CpG binding protein 2 (Mecp2).In vivo data showed that delivery of Exo(IPC) significantly reduced cardiac fibrosis.Our data identified a significant benefit of Exo(IPC) for the treatment of cardiac diseases by targeting Mecp2 via miR-22.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Cardiovascular Institute, Southern Medical University, Guangzhou, China ; Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.

ABSTRACT
Mesenchymal stem cells (MSCs) have potential application for the treatment of ischemic heart diseases. Besides differentiation properties, MSCs protect ischemic cardiomyocytes by secretion of paracrine factors. In this study, we found exosomes enriched with miR-22 were secreted by MSCs following ischemic preconditioning (Exo(IPC)) and mobilized to cardiomyocytes where they reduced their apoptosis due to ischemia. Interestingly, by time-lapse imaging, we for the first time captured the dynamic shedding of miR-22 loaded exosomes from cytosol to extracellular space. Furthermore, the anti-apoptotic effect of miR-22 was mediated by direct targeting of methyl CpG binding protein 2 (Mecp2). In vivo data showed that delivery of Exo(IPC) significantly reduced cardiac fibrosis. Our data identified a significant benefit of Exo(IPC) for the treatment of cardiac diseases by targeting Mecp2 via miR-22.

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ExoIPC ameliorated cardiac fibrosis.A. Masson trichrome staining to determine the infarct size in various groups. B. Quantification of infarct size in various groups. (*) denotes P<0.05 vs. Scr for significant difference. (#) denotes P<0.05 vs. si-Mecp2, miR-22 mimic, Exonon-IPC, ExoIPC+miR-22 inhi for significant difference (n = 8). (∥) denotes P<0.01 vs. Exonon-IPC for significant difference (n = 8 for each group).
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pone-0088685-g005: ExoIPC ameliorated cardiac fibrosis.A. Masson trichrome staining to determine the infarct size in various groups. B. Quantification of infarct size in various groups. (*) denotes P<0.05 vs. Scr for significant difference. (#) denotes P<0.05 vs. si-Mecp2, miR-22 mimic, Exonon-IPC, ExoIPC+miR-22 inhi for significant difference (n = 8). (∥) denotes P<0.01 vs. Exonon-IPC for significant difference (n = 8 for each group).

Mentions: In order to confirm the role of miR-22 loaded exosomes in heart repair, we injected scramble, si-Mecp2, miR-22 mimic, and ExoIPC, Exonon-IPC, ExoIPC+ miR-22 inhi into infarcted hearts. Masson trichrome staining showed delivery of si-Mecp2 and miR-22 mimic significantly reduced cardiac fibrosis as compared to scramble. Delivery of miR-22 loaded exosomes resulted in significant reduction of fibrotic area as compared to Exonon-IPC, si-Mecp2, miR-22 mimic. However, delivery of exosomes from MSCs after inhibition of miR-22 prior to IPC (ExoIPC+ miR-22 inhi) mitigated anti-fibrotic effects (Fig. 5A and B). Taken together, miR-22 is a critical factor in mediating the cardioprotective effect of ExoIPC on cardiac remodeling post myocardial infarction via targeting Mecp2.


Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22.

Feng Y, Huang W, Wani M, Yu X, Ashraf M - PLoS ONE (2014)

ExoIPC ameliorated cardiac fibrosis.A. Masson trichrome staining to determine the infarct size in various groups. B. Quantification of infarct size in various groups. (*) denotes P<0.05 vs. Scr for significant difference. (#) denotes P<0.05 vs. si-Mecp2, miR-22 mimic, Exonon-IPC, ExoIPC+miR-22 inhi for significant difference (n = 8). (∥) denotes P<0.01 vs. Exonon-IPC for significant difference (n = 8 for each group).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928277&req=5

pone-0088685-g005: ExoIPC ameliorated cardiac fibrosis.A. Masson trichrome staining to determine the infarct size in various groups. B. Quantification of infarct size in various groups. (*) denotes P<0.05 vs. Scr for significant difference. (#) denotes P<0.05 vs. si-Mecp2, miR-22 mimic, Exonon-IPC, ExoIPC+miR-22 inhi for significant difference (n = 8). (∥) denotes P<0.01 vs. Exonon-IPC for significant difference (n = 8 for each group).
Mentions: In order to confirm the role of miR-22 loaded exosomes in heart repair, we injected scramble, si-Mecp2, miR-22 mimic, and ExoIPC, Exonon-IPC, ExoIPC+ miR-22 inhi into infarcted hearts. Masson trichrome staining showed delivery of si-Mecp2 and miR-22 mimic significantly reduced cardiac fibrosis as compared to scramble. Delivery of miR-22 loaded exosomes resulted in significant reduction of fibrotic area as compared to Exonon-IPC, si-Mecp2, miR-22 mimic. However, delivery of exosomes from MSCs after inhibition of miR-22 prior to IPC (ExoIPC+ miR-22 inhi) mitigated anti-fibrotic effects (Fig. 5A and B). Taken together, miR-22 is a critical factor in mediating the cardioprotective effect of ExoIPC on cardiac remodeling post myocardial infarction via targeting Mecp2.

Bottom Line: Furthermore, the anti-apoptotic effect of miR-22 was mediated by direct targeting of methyl CpG binding protein 2 (Mecp2).In vivo data showed that delivery of Exo(IPC) significantly reduced cardiac fibrosis.Our data identified a significant benefit of Exo(IPC) for the treatment of cardiac diseases by targeting Mecp2 via miR-22.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Cardiovascular Institute, Southern Medical University, Guangzhou, China ; Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.

ABSTRACT
Mesenchymal stem cells (MSCs) have potential application for the treatment of ischemic heart diseases. Besides differentiation properties, MSCs protect ischemic cardiomyocytes by secretion of paracrine factors. In this study, we found exosomes enriched with miR-22 were secreted by MSCs following ischemic preconditioning (Exo(IPC)) and mobilized to cardiomyocytes where they reduced their apoptosis due to ischemia. Interestingly, by time-lapse imaging, we for the first time captured the dynamic shedding of miR-22 loaded exosomes from cytosol to extracellular space. Furthermore, the anti-apoptotic effect of miR-22 was mediated by direct targeting of methyl CpG binding protein 2 (Mecp2). In vivo data showed that delivery of Exo(IPC) significantly reduced cardiac fibrosis. Our data identified a significant benefit of Exo(IPC) for the treatment of cardiac diseases by targeting Mecp2 via miR-22.

Show MeSH
Related in: MedlinePlus