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Published on: September 15, 2023
Exosomes from mesenchymal stem cells overexpressing MIF enhance myocardial repair
Xiaolin Liu1, Xin Li2,3, Wenwu Zhu1
1Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Abstract:
Accumulating evidence has shown that mesenchymal stem cell (MSC)-derived exosomes (exo) mediate cardiac repair following myocardial infarction (MI). Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, plays a critical role in regulating cell homeostasis. This study aimed to investigate the cardioprotective effects of exo secreted from bone marrow-MSCs (BM-MSCs) overexpressing MIF in a rat model of MI. MIF plasmid was transducted in BM-MSCs. Exo were isolated from the supernatants of BM-MSCs and MIF-BM-MSCs, respectively. The morphology of mitochondria in neonatal mice cardiomyocytes (NRCMs) was determined by MitoTracker staining. The apoptosis of NRCMs was examined by deoxynucleotidyl transferase-mediated dUTP nick end-labeling. BM-MSC-exo and MIF-BM-MSC-exo were intramuscularly injected into the peri-infarct region in a rat model of MI. The heart function of rats was assessed by echocardiography. The expression of MIF was greatly enhanced in MIF-BM-MSCs compared with BM-MSCs. Both BM-MSC-exo and MIF-BM-MSC-exo expressed CD63 and CD81. NRCMs treated with MIF-BM-MSC-exo exhibited less mitochondrial fragmentation and cell apoptosis under hypoxia/serum deprivation (H/SD) challenge than those treated with BM-MSC-exo via activating adenosine 5'-monophosphate-activated protein kinase signaling. Moreover, these effects were partially abrogated by Compound C. Injection of BM-MSC-exo or MIF-BM-MSC-exo greatly restored heart function in a rat model of MI. Compared with BM-MSC-exo, injection of MIF-BM-MSC-exo was associated with enhanced heart function, reduced heart remodeling, less cardiomyocyte mitochondrial fragmentation, reactive oxygen species generation, and apoptosis. Our study reveals a new mechanism of MIF-BM-MSC-exo-based therapy for MI and provides a novel strategy for cardiovascular disease treatment.
Insights
Mesenchymal stem cell (MSC)-derived exosomes overexpressing macrophage migration inhibitory factor (MIF) enhance cardiac repair after myocardial infarction (MI). These exosomes protect cardiomyocytes and improve heart function, offering a novel cardiovascular disease treatment strategy.
Area of Science:
- Regenerative Medicine
- Cardiovascular Biology
- Cell Biology
Background:
- Mesenchymal stem cell (MSC)-derived exosomes (exo) show promise in mediating cardiac repair post-myocardial infarction (MI).
- Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, is crucial for cellular homeostasis.
- Investigating MIF's role in MSC-exo for MI treatment is a key area for cardiovascular disease research.
Purpose of the Study:
- To evaluate the cardioprotective effects of exosomes derived from bone marrow-MSCs (BM-MSCs) engineered to overexpress MIF.
- To explore the therapeutic potential of MIF-overexpressing BM-MSC-exo in a rat model of MI.
- To elucidate the underlying mechanisms of MIF-BM-MSC-exo in protecting cardiomyocytes and improving cardiac function.
Main Methods:
- Bone marrow-MSCs were transduced with a MIF plasmid to generate MIF-overexpressing BM-MSCs.
- Exosomes were isolated from BM-MSC and MIF-BM-MSC supernatants and characterized (e.g., CD63, CD81 expression).
- Cardiomyocyte apoptosis and mitochondrial morphology were assessed in vitro; cardiac function and remodeling were evaluated in a rat MI model post-exosome injection.
Main Results:
- MIF expression was significantly enhanced in MIF-BM-MSCs.
- MIF-BM-MSC-exo treatment reduced mitochondrial fragmentation and apoptosis in cardiomyocytes under hypoxia/serum deprivation, partly via activating AMP-activated protein kinase (AMPK) signaling.
- In vivo, MIF-BM-MSC-exo injection improved cardiac function, reduced cardiac remodeling, and decreased cardiomyocyte mitochondrial damage, reactive oxygen species generation, and apoptosis compared to BM-MSC-exo.
Conclusions:
- Exosomes derived from MIF-overexpressing BM-MSCs exhibit enhanced cardioprotective effects in a rat MI model.
- MIF-BM-MSC-exo therapy protects cardiomyocytes by preserving mitochondrial integrity and reducing apoptosis, partly through AMPK activation.
- This study presents a novel therapeutic strategy using engineered exosomes for treating myocardial infarction and cardiovascular diseases.
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