title: Hypoxia regulates the therapeutic potential of mesenchymal stem cells through enhanced autophagy.
abstract: Bone marrow-derived mesenchymal stem cells (BM-MSCs)have great therapeutic potential for the repair of diabetic lower-limb ischemia because of their proangiogenic properties. However, cells transplanted into an ischemic environment have reduced cell survival rates and impaired angiogenic capacity in vivo. We explored hypoxia pretreatment as a method to promote BM-MSC survival by inducing autophagy. Our results showed that hypoxic pretreatment has no effect on the phenotype or differentiation capacity of BM-MSCs; however, hypoxia increased viability and reduced apoptosis in cells treated with lipopolysaccharide. Immunofluorescence and western blot results showed that hypoxia pretreatment enhances cell autophagy mediated by elevated expression of hypoxia inducible factor-1α (HIF-1α). The AMPK/mTOR (adenosine monophosphate-activated protein kinase/mammalian target of rapamycin) signaling pathway was also activated in BM-MSCs during hypoxia-enhanced autophagy. It is important to note that hypoxia pretreatment in BM-MSCs significantly enhanced cell survival and promoted angiogenesis in the lower limb of ischemic diabetic rats. In conclusion, hypoxia pretreatment enhances survival in BM-MSCs, promoting angiogenesis by increasing autophagy and significantly decreasing apoptosis. Therefore, modulation of autophagy with hypoxic pretreatment may provide a novel strategy to improve MSC-based therapies.
authors.affiliation: Chinese PLA General Hospital, Beijing, China.
authors.forename: Jiejie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Chinese PLA General Hospital, Beijing, China.
authors.forename: Haojie
authors.initials: H
authors.lastname: Hao
authors.affiliation: Chinese PLA General Hospital, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Huang
authors.affiliation: Chinese PLA General Hospital, Beijing, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Tong
authors.affiliation: Chinese PLA General Hospital, Beijing, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Ti
authors.affiliation: Chinese PLA General Hospital, Beijing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Dong
authors.affiliation: Chinese PLA General Hospital, Beijing, China.
authors.forename: Deyun
authors.initials: D
authors.lastname: Chen
authors.affiliation: Hainan Branch of Chinese PLA General Hospital, Sanya, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Chinese PLA General Hospital, Beijing, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Liu
authors.affiliation: Chinese PLA General Hospital, Beijing, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Han
authors.affiliation: Chinese PLA General Hospital, Beijing, China fuxiaobing@vip.sina.com hanwdrsw@sina.com.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Fu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002454:Cell Differentiation; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D012313:RNA / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D012313:RNA; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK/mTOR signaling; autophagy; bone marrow–derived mesenchymal stem cells; hypoxia