title: Macrophage migration inhibitory factor promotes cardiac stem cell proliferation and endothelial differentiation through the activation of the PI3K/Akt/mTOR and AMPK pathways.
abstract: Macrophage migration inhibitory factor (MIF) has pleiotropic immune functions in a number of inflammatory diseases. Recent evidence from expression and functional studies has indicated that MIF is involved in various aspects of cardiovascular disease. In this study, we aimed to determine whether MIF supports in vitro c-kit+CD45- cardiac stem cell (CSC) survival, proliferation and differentiation into endothelial cells, as well as the possible mechanisms involved. We observed MIF receptor (CD74) expression in mouse CSCs (mCSCs) using PCR and immunofluorescence staining, and MIF secretion by mCSCs using PCR and ELISA in vitro. Increasing amounts of exogenous MIF did not affect CD74 expression, but promoted mCSC survival, proliferation and endothelial differentiation. By contrast, treatment with an MIF inhibitor (ISO-1) or siRNA targeting CD74 (CD74‑siRNA) suppressed the biological changes induced by MIF in the mCSCs. Increasing amounts of MIF increased the phosphorylation of Akt and mammalian target of rapamycin (mTOR), which are known to support cell survival, proliferation and differentiation. These effects of MIF on the mCSCs were abolished by LY294002 [a phosphoinositide 3-kinase (PI3K) inhibitor] and MK-2206 (an Akt inhibitor). Moreover, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation increased following treatment with MIF. The AMPK inhibitor, compound C, partly blocked the pro-proliferative effects of MIF on the mCSCs. In conclusion, our results suggest that MIF promotes mCSC survival, proliferation and endothelial differentiation through the activation of the PI3K/Akt/mTOR and AMPK signaling pathways. Thus, MIF may prove to be a potential therapeutic factor in the treatment of heart failure and myocardial infarction by activating CSCs.
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Fengyun
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Yongshun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Jingjin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Ming
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Lv
authors.affiliation: The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Shaohong
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers; D002454:Cell Differentiation; D049109:Cell Proliferation; D015870:Gene Expression; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D051379:Mice; D032386:Myoblasts, Cardiac / Q000166:cytology* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D055372:AMP-Activated Protein Kinases; D000944:Antigens, Differentiation, B-Lymphocyte; D015415:Biomarkers; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C045084:invariant chain