Hypoxia promotes bone marrow-derived mesenchymal stem cell proliferation through apelin/APJ/autophagy pathway.
Bone marrow-derived mesenchymal stem cells (BMSCs) are a population of multipotent progenitors that have the capacity of proliferation and differentiation into mesenchymal lineage cells. The regulatory peptide apelin is the endogenous ligand for the G protein-coupled receptor APJ. Apelin, which can enhance BMSC proliferation, has mitogenic effects on a wide variety of cell types. We hypothesized that the increased apelin/APJ might be involved in the occurrence and development of hypoxia-induced BMSC proliferation. BMSCs from the bone marrow of 8- to 10-week-old C57BL/6J mice were cultured under either normoxia (21% oxygen) or hypoxia (1% oxygen) condition. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 5-bromo-2'-deoxyuridine assay. Expressions of hypoxia-inducible factor (HIF)-1α, apelin, APJ, Beclin-1, and LC3II/LC3I were detected by western blot analysis. Results suggested that hypoxia enhanced the proliferation of BMSC in a time-dependent manner. The expressions of HIF-1α, apelin, APJ, Beclin-1, and LC3II/LC3I were increased in BMSCs induced by hypoxia. Small interfering RNA (siRNA)-HIF-1α that inhibited the hypoxia-induced expressions of apelin, APJ, Beclin-1, and LC3II/LC3I prevented hypoxia-induced BMSC proliferation. siRNA-APJ that inhibited the hypoxia-induced expressions of Beclin-1 and LC3II/LC3I reversed hypoxia-induced BMSC proliferation. siRNA-Beclin-1 also abolished hypoxia-induced cell proliferation. These data suggested that the apelin/APJ/autophagy signaling pathway might be involved in hypoxia-induced BMSC proliferation.
Post-doctoral Mobile Stations for Basic Medicine, Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China.
Lanfang
L
Li
Institute of Pathogenic Biology, University of South China, Hengyang 421001, China.
Lifang
L
Li
College of Public Health and Social Justice, Saint Louis University, Saint Louis, MO 63108, USA.
Zidong
Z
Zhang
Post-doctoral Mobile Stations for Basic Medicine, Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China z_sjiang@126.com.
Zhisheng
Z
Jiang
D054392:Adipokines / Q000378:metabolism*; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D001343:Autophagy; D001853:Bone Marrow / Q000378:metabolism*; D015687:Cell Hypoxia; D049109:Cell Proliferation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
D054392:Adipokines; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled
apelin; autophagy; hypoxia; mesenchymal stem cell; proliferation