title: Improved survival of mesenchymal stem cells by macrophage migration inhibitory factor.
abstract: Macrophage migration inhibitory factor (MIF) is a critical inflammatory cytokine that was recently associated with progenitor cell survival and potently inhibits apoptosis. We examined the protective effect of MIF on hypoxia/serum deprivation (SD)-induced apoptosis of mesenchymal stem cells (MSCs), as well as the possible mechanisms. MSCs were obtained from rat bone marrow and cultured in vitro. Apoptosis was induced by culturing MSCs under hypoxia/SD conditions for up to 24 h and assessed by flow cytometry. Expression levels of c-Met, Akt, and FOXO3a were detected by Western blotting. CD74 expression was detected by qRT-PCR, Western blot, and immunofluorescence. Oxidative stress under hypoxia/SD was examined by detection of reactive oxygen species (ROS) and activity of superoxide dismutase (SOD) and malondialdehyde (MDA). Hypoxia/SD-induced apoptosis was significantly attenuated by recombinant rat MIF in a concentration-dependent manner. MIF induced CD74-asssociated c-Met activation, which was blocked by knocking down CD74 expression using siRNA. MIF also induced Akt and associated FOXO3a phosphorylation, and this effect was abolished by knocking down either CD74 or Akt. In addition, MIF decreased oxidative stress in MSCs, as shown by decreased ROS and MDA, and increased the activity of SOD. Knockdown of CD74, Akt, or FOXO3a largely attenuated the anti-apoptotic effect of MIF and its ability to protect against oxidative stress. MIF protected MSCs from hypoxia/SD-induced apoptosis by interacting with CD74 to stimulate c-Met, leading to downstream PI3K/Akt-FOXO3a signaling and decreased oxidative stress.
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
authors.forename: Wenzheng
authors.initials: W
authors.lastname: Xia
authors.forename: Congying
authors.initials: C
authors.lastname: Xie
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Jiang
authors.forename: Meng
authors.initials: M
authors.lastname: Hou
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics; D017209:Apoptosis; D049109:Cell Proliferation / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis* / Q000235:genetics; D008315:Malondialdehyde / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D017382:Reactive Oxygen Species; C045084:invariant chain; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D019859:Proto-Oncogene Proteins c-met; D019746:Intramolecular Oxidoreductases; C515599:Mif protein, rat