Science China Life Sciences

, Volume 57, Issue 2, pp 171–180 | Cite as

Increased leptin by hypoxic-preconditioning promotes autophagy of mesenchymal stem cells and protects them from apoptosis

  • LiHan Wang
  • XinYang Hu
  • Wei Zhu
  • Zhi Jiang
  • Yu Zhou
  • PanPan Chen
  • JianAn WangEmail author
Open Access
Research Paper Thematic Issue: Stem cells and regenerative medicine in China


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.


BMSCs autophagy hypoxic-preconditioning leptin apoptosis 


  1. 1.
    Hu X, Yu SP, Fraser JL, Lu Z, Ogle ME, Wang JA, Wei L. Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J Thorac Cardiovasc Surg, 2008, 135: 799–808PubMedCrossRefGoogle Scholar
  2. 2.
    Chang CP, Chio CC, Cheong CU, Chao CM, Cheng BC, Lin MT. Hypoxic preconditioning enhances the therapeutic potential of the secretome from cultured human mesenchymal stem cells in experimental traumatic brain injury. Clin Sci (Lond), 2013, 124: 165–176CrossRefGoogle Scholar
  3. 3.
    Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med, 2013, 368: 1845–1846PubMedCrossRefGoogle Scholar
  4. 4.
    Li ZL, Lerman LO. Impaired myocardial autophagy linked to energy metabolism disorders. Autophagy, 2012, 8: 992–994PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Zhang Q, Yang YJ, Wang H, Dong QT, Wang TJ, Qian HY, Xu H. Autophagy activation: a novel mechanism of atorvastatin to protect mesenchymal stem cells from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway. Stem Cells Dev, 2012, 21: 1321–1332PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Hu YL, DeLay M, Jahangiri A, Molinaro AM, Rose SD, Carbonell WS, Aghi MK. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res, 2012, 72: 1773–1783PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Wang B, Wood IS, Trayhurn P. Hypoxia induces leptin gene expression and secretion in human preadipocytes: differential effects of hypoxia on adipokine expression by preadipocytes. J Endocrinol, 2008, 198: 127–134PubMedCrossRefGoogle Scholar
  8. 8.
    Grosfeld A, Andre J, Hauguel-De Mouzon S, Berra E, Pouyssegur J, Guerre-Millo M. Hypoxia-inducible factor 1 transactivates the human leptin gene promoter. J Biol Chem, 2002, 277: 42953–42957PubMedCrossRefGoogle Scholar
  9. 9.
    Ahima RS, Flier JS. Leptin. Annu Rev Physiol, 2000, 62: 413–437PubMedCrossRefGoogle Scholar
  10. 10.
    Myers MG, Cowley MA, Munzberg H. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol, 2008, 70: 537–556PubMedCrossRefGoogle Scholar
  11. 11.
    Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature, 2002, 415: 339–343PubMedCrossRefGoogle Scholar
  12. 12.
    Steinberg GR, Rush JW, Dyck DJ. AMPK expression and phosphorylation are increased in rodent muscle after chronic leptin treatment. Am J Physiol Endocrinol Metab, 2003, 284: E648–654PubMedCrossRefGoogle Scholar
  13. 13.
    Malik SA, Marino G, BenYounes A, Shen S, Harper F, Maiuri MC, Kroemer G. Neuroendocrine regulation of autophagy by leptin. Cell Cycle, 2011, 10: 2917–2923PubMedCrossRefGoogle Scholar
  14. 14.
    Mizushima N. Methods for monitoring autophagy. Int J Biochem Cell Biol, 2004, 36: 2491–2502PubMedCrossRefGoogle Scholar
  15. 15.
    Knoepfler PS. Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine. Stem Cells, 2009, 27: 1050–1056PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Ding DC, Shyu WC, Lin SZ. Mesenchymal stem cells. Cell Transplant, 2011, 20: 5–14PubMedCrossRefGoogle Scholar
  17. 17.
    Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J, 2012, 441: 523–540PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Mazure NM, Pouyssegur J. Hypoxia-induced autophagy: cell death or cell survival? Curr Opin Cell Biol, 2010, 22: 177–180PubMedCrossRefGoogle Scholar
  19. 19.
    Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem, 2008, 283: 10892–10903PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Sanchez CG, Penfornis P, Oskowitz AZ, Boonjindasup AG, Cai DZ, Dhule SS, Rowan BG, Kelekar A, Krause DS, Pochampally RR. Activation of autophagy in mesenchymal stem cells provides tumor stromal support. Carcinogenesis, 2011, 32: 964–972PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, Gottlieb RA, Gustafsson AB. Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ, 2007, 14: 146–157PubMedCrossRefGoogle Scholar
  22. 22.
    Gurusamy N, Lekli I, Mukherjee S, Ray D, Ahsan MK, Gherghiceanu M, Popescu LM, Das DK. Cardioprotection by resveratrol: a novel mechanism via autophagy involving the mTORC2 pathway. Cardiovasc Res, 2010, 86: 103–112PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Kanamori H, Takemura G, Goto K, Maruyama R, Ono K, Nagao K, Tsujimoto A, Ogino A, Takeyama T, Kawaguchi T, Watanabe T, Kawasaki M, Fujiwara T, Fujiwara H, Seishima M, Minatoguchi S. Autophagy limits acute myocardial infarction induced by permanent coronary artery occlusion. Am J Physiol Heart Circ Physiol, 2011, 300: H2261–2271PubMedCrossRefGoogle Scholar
  24. 24.
    Loos B, Genade S, Ellis B, Lochner A, Engelbrecht AM. At the core of survival: autophagy delays the onset of both apoptotic and necrotic cell death in a model of ischemic cell injury. Exp Cell Res, 2011, 317: 1437–1453PubMedCrossRefGoogle Scholar
  25. 25.
    Guo Z, Jiang H, Xu X, Duan W, Mattson MP. Leptin-mediated cell survival signaling in hippocampal neurons mediated by JAK STAT3 and mitochondrial stabilization. J Biol Chem, 2008, 283: 1754–1763PubMedCrossRefGoogle Scholar
  26. 26.
    Magarinos MP, Sanchez-Margalet V, Kotler M, Calvo JC, Varone CL. Leptin promotes cell proliferation and survival of trophoblastic cells. Biol Reprod, 2007, 76: 203–210PubMedCrossRefGoogle Scholar
  27. 27.
    Yu SW, Baek SH, Brennan RT, Bradley CJ, Park SK, Lee YS, Jun EJ, Lookingland KJ, Kim EK, Lee H, Goudreau JL, Kim SW. Autophagic death of adult hippocampal neural stem cells following insulin withdrawal. Stem Cells, 2008, 26: 2602–2610PubMedCrossRefGoogle Scholar
  28. 28.
    Carloni S, Buonocore G, Balduini W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol Dis, 2008, 32: 329–339PubMedCrossRefGoogle Scholar
  29. 29.
    Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol, 2010, 22: 124–131PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Wang D, Chen J, Chen H, Duan Z, Xu Q, Wei M, Wang L, Zhong M. Leptin regulates proliferation and apoptosis of colorectal carcinoma through PI3K/Akt/mTOR signalling pathway. J Biosci, 2012, 37: 91–101PubMedCrossRefGoogle Scholar
  31. 31.
    Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW, Myers MG Jr. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature, 2003, 421: 856–859PubMedCrossRefGoogle Scholar
  32. 32.
    Huang F, Xiong X, Wang H, You S, Zeng H. Leptin-induced vascular smooth muscle cell proliferation via regulating cell cycle, activating ERK1/2 and NF-kappaB. Acta Biochim Biophys Sin (Shanghai), 2010, 42: 325–331CrossRefGoogle Scholar

Copyright information

© The Author(s) 2014

Authors and Affiliations

  • LiHan Wang
    • 1
  • XinYang Hu
    • 1
  • Wei Zhu
    • 1
  • Zhi Jiang
    • 1
  • Yu Zhou
    • 1
  • PanPan Chen
    • 1
  • JianAn Wang
    • 1
    Email author
  1. 1.Cardiovascular Key Lab of Zhejiang Province; the Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina

Personalised recommendations