title: Granulocyte colony-stimulating factor activating HIF-1alpha acts synergistically with erythropoietin to promote tissue plasticity.
abstract: Stroke and peripheral limb ischemia are serious clinical problems with poor prognosis and limited treatment. The cytokines erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) have been used to induce endogenous cell repair and angiogenesis. Here, we demonstrated that the combination therapy of EPO and G-CSF exerted synergistic effects on cell survival and functional recovery from cerebral and peripheral limbs ischemia. We observed that even under normoxic conditions, G-CSF activates hypoxia-inducible factor-1alpha (HIF-1alpha), which then binds to the EPO promoter and enhances EPO expression. Serum EPO level was significantly increased by G-CSF injection, with the exception of Tg-HIF-1alpha(+f/+f) mice. The neuroplastic mechanisms exerted by EPO combined with G-CSF included enhanced expression of the antiapoptotic protein of Bcl-2, augmented neurotrophic factors synthesis, and promoted neovascularization. Further, the combination therapy significantly increased homing and differentiation of bone marrow stem cells (BMSCs) and intrinsic neural progenitor cells (INPCs) into the ischemic area. In summary, EPO in combination with G-CSF synergistically enhanced angiogenesis and tissue plasticity in ischemic animal models, leading to greater functional recovery than either agent alone.
authors.affiliation: Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Liu
authors.forename: Shin-Da
authors.initials: SD
authors.lastname: Lee
authors.forename: Hsu-Tung
authors.initials: HT
authors.lastname: Lee
authors.forename: Demeral David
authors.initials: DD
authors.lastname: Liu
authors.forename: Hsiao-Jung
authors.initials: HJ
authors.lastname: Wang
authors.forename: Ren-Shyan
authors.initials: RS
authors.lastname: Liu
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
authors.forename: Ching-Yuan
authors.initials: CY
authors.lastname: Su
authors.forename: Hung
authors.initials: H
authors.lastname: Li
authors.forename: Woei-Cherng
authors.initials: WC
authors.lastname: Shyu
mesh_terms: D000818:Animals; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004921:Erythropoietin / Q000235:genetics / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects*; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism* / Q000502:physiology; D007511:Ischemia / Q000188:drug therapy*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011401:Promoter Regions, Genetic; D013234:Stem Cells / Q000187:drug effects
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor
references.citation: Cancer Res. 2000 Aug 1;60(15):4010-5
references.pmid: 10945599
references.citation: Circ Res. 2001 Jul 6;89(1):47-54
references.pmid: 11440977
references.citation: J Clin Invest. 2005 Aug;115(8):2083-98
references.pmid: 16007267
references.citation: Stroke. 2002 May;33(5):1362-8
references.pmid: 11988616
references.citation: Nat Med. 2006 May;12(5):557-67
references.pmid: 16648859
references.citation: J Exp Med. 2003 Nov 3;198(9):1391-402
references.pmid: 14597738
references.citation: Br J Haematol. 2004 Jan;124(2):190-4
references.pmid: 14687029
references.citation: Brain Res. 2006 Feb 16;1073-1074:190-201
references.pmid: 16423324
references.citation: Stroke. 2004 Jul;35(7):1732-7
references.pmid: 15178821
references.citation: J Neurosci. 2005 Feb 16;25(7):1769-77
references.pmid: 15716413
references.citation: J Cereb Blood Flow Metab. 2006 Apr;26(4):556-64
references.pmid: 16136056
references.citation: Ann Hematol. 2006 Mar;85(3):174-80
references.pmid: 16408206
references.citation: Blood. 1994 Dec 15;84(12):4157-63
references.pmid: 7527670
references.citation: Cochrane Database Syst Rev. 2006 Jul 19;(3):CD005207
references.pmid: 16856086
references.citation: Diabetologia. 2006 May;49(5):1049-63
references.pmid: 16506055
references.citation: Brain Res. 2005 May 31;1045(1-2):22-30
references.pmid: 15910759
references.citation: J Biol Chem. 2000 Sep 1;275(35):26765-71
references.pmid: 10837481
references.citation: Psychoneuroendocrinology. 2006 Jan;31(1):38-48
references.pmid: 15996825
references.citation: Neuroreport. 2004 Jun 7;15(8):1225-9
references.pmid: 15167538
references.citation: Cardiovasc Res. 2007 Mar 1;73(4):823-32
references.pmid: 17258698
references.citation: J Neurosci. 2001 Jun 1;21(11):3895-903
references.pmid: 11356877
references.citation: Blood. 2004 Jul 15;104(2):321-7
references.pmid: 15054036
references.citation: J Clin Oncol. 1999 Apr;17(4):1288
references.pmid: 10561191
references.citation: J Biol Chem. 1996 Dec 13;271(50):32253-9
references.pmid: 8943284
references.citation: J Mol Cell Cardiol. 2007 Jun;42(6):1036-44
references.pmid: 17498737
references.citation: Blood. 2005 Jun 1;105(11):4258-63
references.pmid: 15705785
references.citation: Blood. 1998 May 1;91(9):3222-9
references.pmid: 9558377
references.citation: Brain Res. 2005 Apr 18;1041(2):125-31
references.pmid: 15829221
references.citation: J Neurochem. 2006 Jan;96(2):428-43
references.pmid: 16336625
references.citation: Brain Res. 2005 Oct 5;1058(1-2):120-8
references.pmid: 16150422
references.citation: J Mol Cell Cardiol. 2007 Mar;42(3):540-8
references.pmid: 17223129
references.citation: Blood. 1991 Oct 15;78(8):1954-62
references.pmid: 1717076
references.citation: Blood. 1999 Sep 1;94(5):1561-7
references.pmid: 10477681
references.citation: Circulation. 2004 Sep 28;110(13):1847-54
references.pmid: 15381647
references.citation: FASEB J. 2005 Dec;19(14):2005-7
references.pmid: 16223785
references.citation: J Cereb Blood Flow Metab. 2007 May;27(5):1043-54
references.pmid: 17077815
references.citation: J Clin Invest. 2008 Jan;118(1):133-48
references.pmid: 18079966
references.citation: Neurosci Lett. 2007 May 18;418(3):248-52
references.pmid: 17449175
references.citation: J Biol Chem. 2002 Nov 1;277(44):41750-5
references.pmid: 12205091
references.citation: J Interferon Cytokine Res. 2005 Nov;25(11):674-83
references.pmid: 16318581
references.citation: Drugs. 1994 Nov;48(5):731-60
references.pmid: 7530630
references.citation: Circ Res. 2005 Jun 10;96(11):1145-51
references.pmid: 15879308
references.citation: Circulation. 2004 Mar 30;109(12):1543-9
references.pmid: 15023891
references.citation: Nature. 1992 Oct 29;359(6398):843-5
references.pmid: 1279431
references.citation: Stroke. 2007 Sep;38(9):2584-91
references.pmid: 17656664
references.citation: J Pharmacol Exp Ther. 2006 Apr;317(1):109-16
references.pmid: 16357210
references.citation: Circulation. 2006 Feb 7;113(5):701-10
references.pmid: 16461843
references.citation: FASEB J. 2005 Feb;19(2):307-9
references.pmid: 15574488
references.citation: J Exp Biol. 2000 Apr;203(Pt 8):1253-63
references.pmid: 10729275
references.citation: J Neurosci. 2001 Dec 15;21(24):9733-43
references.pmid: 11739582
references.citation: Int J Biochem Cell Biol. 2005 Mar;37(3):535-40
references.pmid: 15618010
references.citation: Blood. 2007 Mar 15;109(6):2565-70
references.pmid: 17110461