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Delayed Intramyocardial Delivery of Stem Cells after Ischemia Reperfusion Injury in a Murine Model
Published on: September 3, 2020
Exosomal miR-455-3p from BMMSCs prevents cardiac ischemia-reperfusion injury
1Department of Cardiology, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan, China.
Objective:
Bone marrow mesenchymal stem cells (BMMSCs) exert protective effects against myocardial infarction (MI). Here, we focused on the function and mechanism of miR-455-3p from BMMSCs-derived exosomes (BMMSCs-Exo) in myocardial infarction.
Materials And Methods:
BMMSCs were isolated from rat bone marrow, and the exosomes from the culture medium of BMMSCs were separated, and administered to H9C2 cells under hypoxia-reperfusion (H/R) stimulation. MTT and TUNEL staining analyzed cell viability and apoptosis, respectively. RT-qPCR determined miR-455-3p expression. Apoptosis-related proteins, autophagy-associated proteins, and the MEKK1-MKK4-JNK signaling pathway were detected. The interaction between miR-455-3p and MEKK1 was confirmed through dual luciferase activity and RIP assay. An in vivo ischemia reperfusion (I/R) model was established in rats. 2, 3, 5 triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (H&E) staining, Masson staining, and TUNEL staining evaluated the infarct volume and histopathological changes.
Results:
miR-455-3p's expression was down-regulated in BMMSCs-derived exosomes, I/R myocardial tissues, and H/R myocardial cells. miR-455-3p enriched by BMMSC exosomes reduced H/R-mediated cardiomyocyte damage and death-related autophagy. miR-455-3p upregulation suppressed MEKK1-MKK4-JNK. MEKK1 overexpression notably mitigated cell apoptosis, cramped cell viability, suppressed autophagy expansion, and attenuated Exo-miR-455-3p's protection on H/R myocardial cells. In-vivo trials reflected that BMMSC exosomes enriched with miR-455-3p repressed ischemia reperfusion-induced myocardial damage and myocardial cell function.
Conclusion:
miR-455-3p, shuttled by exosomes from MSCs, targets the MEKK1-MKK4-JNK signaling pathway to guard against myocardial ischemia-reperfusion damage.
Insights
Bone marrow mesenchymal stem cell exosomes deliver miR-455-3p to protect against myocardial infarction. This microRNA targets the MEKK1-MKK4-JNK pathway, reducing cell damage and improving heart function after ischemia.
Area of Science:
- Cardiovascular Biology
- Stem Cell Biology
- Molecular Medicine
Background:
- Bone marrow mesenchymal stem cells (BMMSCs) show therapeutic potential for myocardial infarction (MI).
- Exosomes derived from BMMSCs (BMMSCs-Exo) are key mediators of stem cell effects.
- The specific role of microRNAs within BMMSCs-Exo in MI remains under investigation.
Purpose of the Study:
- To investigate the function and mechanism of miR-455-3p delivered by BMMSCs-Exo in myocardial infarction.
- To elucidate the signaling pathway targeted by miR-455-3p in the context of cardiac injury.
Main Methods:
- BMMSCs were isolated, and exosomes were collected and administered to H9C2 cells under hypoxia-reperfusion (H/R) conditions.
- Cell viability, apoptosis, and autophagy were assessed using MTT, TUNEL staining, and protein analysis.
- miR-455-3p expression, MEKK1-MKK4-JNK pathway activation, and exosome-miRNA interactions were analyzed.
- An in vivo rat model of ischemia-reperfusion (I/R) was used to evaluate therapeutic effects.
Main Results:
- miR-455-3p expression was significantly downregulated in BMMSCs-Exo, I/R myocardial tissues, and H/R cells.
- Enrichment of miR-455-3p in BMMSCs-Exo reduced H/R-induced cardiomyocyte damage and autophagy.
- Upregulation of miR-455-3p inhibited the MEKK1-MKK4-JNK pathway.
- MEKK1 overexpression counteracted the protective effects of Exo-miR-455-3p.
- In vivo studies confirmed that BMMSCs-Exo enriched with miR-455-3p attenuated I/R-induced myocardial damage.
Conclusions:
- Exosome-mediated delivery of miR-455-3p by MSCs offers a protective strategy against myocardial ischemia-reperfusion injury.
- The MEKK1-MKK4-JNK signaling pathway is a critical target for miR-455-3p's cardioprotective effects.
