Exosomes from adipose-derived mesenchymal stem cells ameliorate cardiac damage after myocardial infarction by activating S1P/SK1/S1PR1 signaling and promoting macrophage M2 polarization

Abstract

Exosomes derived from mesenchymal stem cells (MSCs) are known to participate in myocardial repair after myocardial infarction (MI), but the mechanism remains unclear. Here, we isolated exosomes from adipose-derived MSCs (ADSCs) and examined their effect on MI-induced cardiac damage. To examine the underlying mechanism, H9c2 cells, cardiac fibroblasts, and HAPI cells were used to study the effect of ADSC-exosomes on hypoxia-induced H9c2 apoptosis, TGF-β1-induced fibrosis of cardiac fibroblasts, and hypoxia-induced macrophage M1 polarization using qRT-PCR, western blot, ELISA, immunohistochemistry, immunofluorescence and flow cytometry. ADSC-exosome treatment mitigated MI-induced cardiac damage by suppressing cardiac dysfunction, cardiac apoptosis, cardiac fibrosis, and inflammatory responses in vitro and in vivo. In addition, ADSC-exosome treatment promoted macrophage M2 polarization. Further experiments found that S1P/SK1/S1PR1 signaling was involved in the ADSC-exosome-mediated myocardial repair. Silencing of S1PR1 reversed the inhibitory effect of ADSC-exosomes on MI-induced cardiac apoptosis and fibrosis in vitro. ADSC-exosome-induced macrophage M2 polarization was also reversed after downregulation of S1PR1 under hypoxia conditions, which promoted NFκB and TGF-β1 expression, and suppressed the MI-induced cardiac fibrosis and inflammatory response. In sum, these results indicate that ADSC-derived exosomes ameliorate cardiac damage after MI by activating S1P/SK1/S1PR1 signaling and promoting macrophage M2 polarization.

Keywords: ADSCs; Exosome; Macrophage; Myocardial infarction; Sphingosine 1-phosphate.