title: A critical role of Src family kinase in SDF-1/CXCR4-mediated bone-marrow progenitor cell recruitment to the ischemic heart.
abstract: The G protein-coupled receptor CXCR4 and its ligand stromal-cell derived factor 1 (SDF-1) play a crucial role in directing progenitor cell (PC) homing to ischemic tissue. The Src family protein kinases (SFK) can be activated by, and serve as effectors of, G proteins. In this study we sought to determine whether SFK play a role in SDF-1/CXCR4-mediated PC homing. First, we investigated whether SDF-1/CXCR4 signaling activates SFK. Bone-marrow mononuclear cells (BM MNCs) were isolated from WT and BM-specific CXCR4-KO mice and treated with SDF-1 and/or CXCR4 antagonist AMD3100. SDF-1 treatment rapidly induced phosphorylation (activation) of hematopoietic Src (i.e., Lyn, Fgr, and Hck) in WT cells but not in AMD3100-treated cells or CXCR4-KO cells. Then, we investigated whether SFK are involved in SDF-1/CXCR4-mediated PC chemotaxis. In a combined chemotaxis and endothelial-progenitor-cell (EPC) colony assay, Src inhibitor SU6656 dose-dependently inhibited the SDF-1-induced migration of colony-forming EPCs. Next, we investigated whether SFK play a role in SDF-1/CXCR4-mediated BM PC homing to the ischemic heart. BM MNCs from CXCR4BAC:eGFP reporter mice were i.v. injected into WT and SDF-1BAC:SDF1-RFP transgenic mice following surgically-induced myocardial infarction (MI). eGFP(+) MNCs and eGFP(+)c-kit(+) PCs that were recruited in the infarct border zone in SDF-1BAC:SDF1-RFP recipients were significantly more than that in WT recipients. Treatments of mice with SU6656 significantly reduced eGFP(+) and eGFP(+)c-kit(+) cell recruitment in both WT and SDF-1BAC:RFP recipients and abrogated the difference between the two groups. Remarkably, PCs isolated from BM-specific C-terminal Src kinase (CSK)-KO (Src activated) mice were recruited more efficiently than PCs from WT PCs in the WT recipients. In conclusion, SFK are activated by SDF-1/CXCR4 signaling and play an essential role in SDF-1/CXCR4-mediated BM PC chemotactic response and ischemic cardiac recruitment.
authors: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China. Electronic address: chengmin_union@hotmail.com.
authors: Min
authors: M
authors: Cheng
authors: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
authors: Kai
authors: K
authors: Huang
authors: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors: Junlan
authors: J
authors: Zhou
authors: Department of Endocrinology, The 2nd Renmin Hospital, Shenzhen, PR China.
authors: Dewen
authors: D
authors: Yan
authors: Vascular Biology Center, Department of Medicine, Medical College of Georgia/Georgia Regents University, Augusta, GA, USA.
authors: Yao-Liang
authors: YL
authors: Tang
authors: Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Boston University, Providence, RI, USA.
authors: Ting C
authors: TC
authors: Zhao
authors: Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors: Richard J
authors: RJ
authors: Miller
authors: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors: Raj
authors: R
authors: Kishore
authors: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors: Douglas W
authors: DW
authors: Losordo
authors: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address: g-qin@northwestern.edu.
authors: Gangjian
authors: G
authors: Qin
mesh_terms: D000818:Animals; D001596:Benzylamines; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics; D000080027:Cyclams; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D007211:Indoles; D019718:Receptors, CXCR4; C416927:SU 6656; D013449:Sulfonamides; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D019009:Proto-Oncogene Proteins c-kit; D019061:src-Family Kinases; C088327:plerixafor
keywords: Bone marrow progenitor cells; CXCR4; Ischemic tissue repair; SDF-1; Src; Stem cell homing
references: J Exp Med. 2002 Sep 2;196(5):667-78
references: 12208881
references: J Biol Chem. 2003 Feb 14;278(7):4847-53
references: 12475982
references: Lancet. 2003 Aug 30;362(9385):697-703
references: 12957092
references: Nat Med. 2004 Aug;10(8):858-64
references: 15235597
references: Cell. 1993 Jun 18;73(6):1125-35
references: 8513497
references: Nature. 1998 Aug 27;394(6696):901-4
references: 9732874
references: EMBO J. 1999 Jul 15;18(14):3964-72
references: 10406801
references: J Am Coll Cardiol. 2014 Jul 1;63(25 Pt A):2873-4
references: 24681138
references: Circ Res. 2005 Nov 25;97(11):1142-51
references: 16254213
references: J Exp Med. 2006 Jan 23;203(1):153-63
references: 16401693
references: Circulation. 2006 Nov 14;114(20):2163-9
references: 17075009
references: J Comp Neurol. 2007 Feb 20;500(6):1007-33
references: 17183554
references: J Leukoc Biol. 2008 Oct;84(4):1082-91
references: 18632989
references: Nature. 2009 Jan 1;457(7225):92-6
references: 19052546
references: Circ Res. 2009 May 22;104(10):1209-16
references: 19407239
references: Circulation. 2010 Jan 19;121(2):325-35
references: 20083719
references: Cell Metab. 2010 Feb 3;11(2):113-24
references: 20142099
references: Neoplasia. 2010 Aug;12(8):599-607
references: 20689754
references: Circ Res. 2010 Oct 29;107(9):1083-93
references: 20847314
references: Cell. 2000 Sep 1;102(5):635-46
references: 11007482