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.

No abstract

Mesenchymal stem cell- (MSC-) based therapy is a novel strategy in regenerative medicine. The functional and regenerative capacities of MSCs decline with senescence. Nonetheless, the potential mechanisms that underlie their senescence are not fully understood. This study was aimed at exploring the potential mechanisms of fibroblast growth factor 21 (FGF21) in the regulation of MSC senescence. The senescence of MSCs was determined by senescence-associated β-galactosidase (SA-β-gal) staining. The morphology and the level of mitochondrial reactive oxygen species (ROS) of MSCs were assessed by MitoTracker and Mito-Sox staining, respectively. The expression of FGF21 and mitochondrial dynamics-related proteins was detected by Western blotting. As MSCs were expanded in vitro, the expression of FGF21 decreased. Depletion of FGF21 enhanced production of mitochondrial reactive oxidative species (ROS) and increased the senescence of early-passage MSCs whereas inhibition of ROS abolished these effects. The senescent MSCs exhibited increased mitochondrial fusion and decreased mitochondrial fission. Treatment of early-passage MSCs with FGF21 siRNA enhanced mitochondrial fusion and reduced mitochondrial fission. Moreover, treatment of mitofusin2- (Mfn2-) siRNA inhibited depletion of FGF21-induced MSC senescence. Furthermore, we demonstrated that depletion of FGF21-induced mitochondrial fusion was regulated by the AMPK signaling pathway. Treatment with an AMPK activator, AICAR, abrogated the depletion of FGF21-induced senescence of MSCs by inhibiting mitochondrial fusion. Compared with MSCs isolated from young donors, those derived from aged donors showed a lower level of FGF21 and a higher level of senescent activity. Furthermore, overexpression of FGF21 in aged MSCs inhibited senescence. Our study shows that FGF21, via the AMPK signaling pathway, regulates the senescence of MSCs by mediating mitochondrial dynamics. Targeting FGF21 might represent a novel strategy to improve the quality and quantity of MSCs.