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Exosomal miR-223 Contributes to Mesenchymal Stem Cell-Elicited Cardioprotection in Polymicrobial Sepsis
Xiaohong Wang1, Haitao Gu1, Dongze Qin1,2
1Department 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.
Insights
Exosomes from mesenchymal stem cells (MSCs) protect the heart during sepsis. This cardio-protection is mediated by exosomal microRNA-223 (miR-223), which targets inflammatory proteins in heart cells.
Area of Science:
- Cardiovascular Biology
- Stem Cell Biology
- Molecular Medicine
Background:
- Mesenchymal stem cells (MSCs) show promise in treating sepsis-induced heart damage.
- The exact mechanisms behind MSC cardio-protection in sepsis are not fully understood.
- MicroRNA-223 (miR-223) is abundant in MSC-derived exosomes, but its role in sepsis is unclear.
Purpose of the Study:
- To investigate the role of exosomal miR-223 in MSC-mediated cardio-protection during sepsis.
- To determine if miR-223 within exosomes is responsible for protecting heart cells from sepsis-induced injury.
Main Methods:
- Sepsis was induced in mice using cecal ligation and puncture (CLP).
- Mesenchymal stem cells with knockout miR-223 (miR-223-KO MSCs) and wild-type MSCs (WT-MSCs) were used.
- Exosomes derived from both miR-223-KO MSCs and WT-MSCs were administered to CLP mice.
- Levels of miR-223, Sema3A, and Stat3 in exosomes and cardiomyocytes were analyzed.
Main Results:
- Mice treated with miR-223-KO MSCs showed no protection against cardiac dysfunction, apoptosis, or inflammation post-CLP.
- WT-MSCs provided cardio-protection, linked to exosome release.
- Exosomes from miR-223-KO MSCs worsened sepsis-induced injury, while WT-MSC exosomes were protective.
- miR-223-KO exosomes contained more Sema3A and Stat3, which were transferred to cardiomyocytes, increasing inflammation and cell death.
Conclusions:
- Exosomal miR-223 is crucial for the cardio-protective effects of MSCs in sepsis.
- WT-MSC-derived exosomes deliver miR-223 to cardiomyocytes, down-regulating Sema3A and Stat3 to prevent injury.
- Loss of exosomal miR-223 abrogates the protective capacity of MSCs in a sepsis model.
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