title: Autophagy regulates the apoptosis of bone marrow-derived mesenchymal stem cells under hypoxic condition via AMP-activated protein kinase/mammalian target of rapamycin pathway.
abstract: Bone marrow-derived mesenchymal stem cells (BM-MSCs) have been demonstrated as an ideal autologous stem cells source for cell-based therapy for myocardial infarction (MI). However, poor viability of donor stem cells after transplantation limits their therapeutic efficiency, whereas the underlying mechanism is still poorly understood. Autophagy, a highly conserved process of cellular degradation, is required for maintaining homeostasis and normal function. Here, we investigated the potential role of autophagy on apoptosis in BM-MSCs induced by hypoxic injury. BM-MSCs, isolated from male C57BL/6 mice, were subjected to hypoxia and serum deprivation (H/SD) injury for 6, 12, and 24 h, respectively. The autophagy state was regulated by 3-methyladenine (3MA) and rapamycin administration. Furthermore, compound C was administrated to inhibit AMPK. The apoptosis induced by H/SD was determined by TUNEL assays. Meanwhile, autophagy was measured by GFP-LC3 plasmids transfection and transmission electron microscope. Moreover, protein expressions were evaluated by Western blot assay. In the present study, we found that hypoxic stress increased autophagy and apoptosis in BM-MSCs time dependently. Meanwhile, hypoxia increased the activity of AMPK/mTOR signal pathway. Moreover, increased apoptosis in BM-MSCs under hypoxia was abolished by 3-MA, whereas was aggravated by rapamycin. Furthermore, the increased autophagy and apoptosis in BM-MSCs induced by hypoxia were abolished by AMPK inhibitor compound C. These data provide evidence that hypoxia induced AMPK/mTOR signal pathway activation which regulated the apoptosis and autophagy in BM-MSCs. Furthermore, the apoptosis of BM-MSCs under hypoxic condition was regulated by autophagy via AMPK/mTOR pathway.
authors.affiliation: Department of Cardiology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: School of Basic Medical Sciences, Taishan Medical University, Taian, Shandong, 271000, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Cardiology, The General Hospital of Chinese People's Liberation Army, Beijing, 100853, China.
authors.forename: Yabin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Orthopaedics and Traumatology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, China.
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China.
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Cardiology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Cardiology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China.
authors.forename: Guojie
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Cardiology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China.
authors.forename: Junke
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China.
authors.forename: Bingwei
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Cardiology, The General Hospital of Chinese People's Liberation Army, Beijing, 100853, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Cao
authors.affiliation: Department of Cardiology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China.
authors.forename: Taohong
authors.initials: T
authors.lastname: Hu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK/mTOR; apoptosis; autophagy; bone marrow-mesenchymal stem cells; hypoxia