Increased leptin by hypoxic-preconditioning promotes autophagy of mesenchymal stem cells and protects them from apoptosis.
Autophagy is the basic catabolic progress involved in cell degradation of unnecessary or dysfunctional cellular components. It has been proven that autophagy could be utilized for cell survival under stresses. Hypoxic-preconditioning (HPC) could reduce apoptosis induced by ischemia and hypoxia/serum deprivation (H/SD) in bone marrow-derived mesenchymal stem cells (BMSCs). Previous studies have shown that both leptin signaling and autophagy activation were involved in the protection against apoptosis induced by various stress, including ischemia-reperfusion. However, it has never been fully understood how leptin was involved in the protective effects conferred by autophagy. In the present study, we demonstrated that HPC can induce autophagy in BMSCs by increased LC3-II/LC3-I ratio and autophagosome formation. Interestingly, similar effects were also observed when BMSCs were pretreated with rapamycin. The beneficial effects offered by HPC were absent when BMSCs were incubated with autophagy inhibitor, 3-methyladenine (3-MA). In addition, down-regulated leptin expression by leptin-shRNA also attenuated HPC-induced autophagy in BMSCs, which in turn was associated with increased apoptosis after exposed to sustained H/SD. Furthermore, increased AMP-activated protein kinase phosphorylation and decreased mammalian target of rapamycin phosphorylation that were observed in HPC-treated BMSCs can also be attenuated by down-regulation of leptin expression. Our data suggests that leptin has impact on HPC-induced autophagy in BMSCs which confers protection against apoptosis under H/SD, possibly through modulating both AMPK and mTOR pathway.
Cardiovascular Key Lab of Zhejiang Province; the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
LiHan
L
Wang
XinYang
X
Hu
Wei
W
Zhu
Zhi
Z
Jiang
Yu
Y
Zhou
PanPan
P
Chen
JianAn
J
Wang
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D055785:Gene Knockdown Techniques; D000860:Hypoxia / Q000378:metabolism*; D019194:Ischemic Preconditioning; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D017931:DNA Primers; D020738:Leptin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase