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Curr Pharm Des. 2019 Jan 19. doi: 10.2174/1381612825666190119130441. [Epub ahead of print]

Human mesenchymal stem cell-derived exosomes reduce ischemia/reperfusion injury by the inhibitions of apoptosis and autophagy.

Author information

1
Huashan Hospital, Fudan University, Shanghai. China.
2
Cardiovascular Research Institute, National University Health System. Singapore.

Abstract

BACKGROUND:

Human mesenchymal stem cell-derived exosomes (hMSC-Exo) have been shown to reduce ischemia/reperfusion injury (I/R) in multiple models. I/R-induced apoptosis or autophagy play important roles in cell death. However, little or no reports demonstrate any roles of hMSC-Exo in this regards.

OBJECTIVE:

To test the hypothesis that the inhibition of I/R-induced apoptosis and autophagy play a pivotal role in the cardioprotection of hMSC-Exo.

METHODS:

Myoblast H9c2 cells and isolated rat hearts were underwent hypoxia /re-oxygenate (H/R) or ischemia/reperfusion (I/R) respectively. H9c2 were treated with 1.0 µg/ml Exo, in comparison with 3-MA or rapamycin (Rapa), a known anti- or pro-autophagic agent respectively. Hearts were treated with 0.5, 1.0 and 2.0 µg/ml Exo for 20 min in the beginning of reperfusion. Cell viability, WST assay, LDH release, Annexin-V staining apoptosis assay and GFP-LC3 labeled autophagosomes formation, cardiac function and Western blot were measured.

RESULTS:

Exo significantly reduced H/R injury as indicated by increased cell viability and reduced LDH and apoptosis. 3-MA, while Rapa, showed increased or decreased protective effects. Rapa-induced injury was partially blocked by Exo. Exo decreased LC3-II/I ratio and increased p62, inhibited autophagosome formation, a sign of autophagy inhibition. In isolated heart, Exo increased cardiac functional recovery and reduced LDH release in I/R. Bcl-2 was significantly upregulated by Exo but not 3-MA. Exo downregulated Traf6 and upregulated mTORC1/p-4eBP1.

CONCLUSION:

Exo reduce I/R-induced apoptosis and autophagy. Up-regulation of Bcl-2 is the cross-talk between these two processes. Inhibition of Traf6 and activation of mTORC1 are additional mechanisms in inhibiting apoptosis and autophagy.

KEYWORDS:

Bcl-2; Exosome; Traf6; autophagy; apoptosis; ischemia/reperfusion; mTOR

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