Journal of Molecular Medicine

, Volume 84, Issue 3, pp 185–193

Effects of G-CSF on left ventricular remodeling and heart failure after acute myocardial infarction

  • Hiroyuki Takano
  • Yingjie Qin
  • Hiroshi Hasegawa
  • Kazutaka Ueda
  • Yuriko Niitsuma
  • Masashi Ohtsuka
  • Issei Komuro


Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic cytokine that promotes proliferation and differentiation of neutrophil progenitors. G-CSF also possesses immunomodulatory properties. G-CSF-induced hematopoietic stem cell mobilization is widely used clinically for transplantation. After it was recently reported that G-CSF mobilizes bone marrow stem cells (BMSCs) into the infarcted hearts and accelerates the differentiation into vascular cells and cardiac myocytes, myocardial regeneration utilizing mobilization of BMSCs by G-CSF is attracting the attention of investigators. In animal models, G-CSF prevents left ventricular remodeling and dysfunction after acute myocardial infarction, at least in part, through a decrease in apoptotic cells and an increase in vascular cells. Although it is controversial whether BMSCs mobilized by G-CSF can differentiate into cardiac myocytes, G-CSF-induced angiogenesis is indeed recognized in infarcted heart. The cardioprotective effects of G-CSF are recognized even in isolated perfused heart. In addition, G-CSF activates various signaling pathways such as Akt, extracellular signal-regulated kinase, and Janus kinase 2/signal transducer and activator of transcription 3 through G-CSF receptors in cardiac myocytes. These observations suggest that G-CSF not only induces mobilization of stem cells and progenitor cells but also acts directly on cardiomyocytes. Therefore, G-CSF may be utilized as a novel agent to have protective and regenerative effects on injured myocardium. Although the effects of G-CSF on the progression of atherosclerosis are still unclear, there is a possibility that G-CSF will become a promising therapy for ischemic heart diseases.


Angiogenesis Cytokine G-CSF Heart failure Myocardial infarction Remodeling 



Acute myocardial infarction


Bone marrow stem cell


Endothelial cell


Endothelial progenitor cell


Extracellular signal-regulated kinase


Granulocyte colony-stimulating factor


G-CSF receptor


Green fluorescent protein


Hematopoietic stem cell


Janus kinase


Left ventricle


Percutaneous coronary intervention


Stem cell factor


Stromal cell-derived factor-1


Signal transducer and activator of transcription


Vascular endothelial growth factor


Vascular smooth muscle cell


  1. 1.
    Jessup M, Brozena S (2003) Heart failure. N Engl J Med 348:2007–2018PubMedCrossRefGoogle Scholar
  2. 2.
    Nian M, Lee P, Khaper N, Liu P (2004) Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res 94:1543–1553PubMedCrossRefGoogle Scholar
  3. 3.
    Papayannopoulou T (2004) Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization. Blood 103:1580–1585PubMedCrossRefGoogle Scholar
  4. 4.
    Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410:701–705PubMedCrossRefGoogle Scholar
  5. 5.
    Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P (2001) Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 98:10344–10349PubMedCrossRefGoogle Scholar
  6. 6.
    Ohtsuka M, Takano H, Zou Y, Toko H, Akazawa H, Qin Y, Suzuki M, Hasegawa H, Nakaya H, Komuro I (2004) Cytokine therapy prevents left ventricular remodeling and dysfunction after myocardial infarction through neovascularization. FASEB J 18:851–853PubMedGoogle Scholar
  7. 7.
    Minatoguchi S, Takemura G, Chen XH, Wang N, Uno Y, Koda M, Arai M, Misao Y, Lu C, Suzuki K, Goto K, Komada A, Takahashi T, Kosai K, Fujiwara T, Fujiwara H (2004) Acceleration of the healing process and myocardial regeneration may be important as a mechanism of improvement of cardiac function and remodeling by postinfarction granulocyte colony-stimulating factor treatment. Circulation 109:2572–2580PubMedCrossRefGoogle Scholar
  8. 8.
    Kawada H, Fujita J, Kinjo K, Matsuzaki Y, Tsuma M, Miyatake H, Muguruma Y, Tsuboi K, Itabashi Y, Ikeda Y, Ogawa S, Okano H, Hotta T, Ando K, Fukuda K (2004) Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood 104:3581–3587PubMedCrossRefGoogle Scholar
  9. 9.
    Iwanaga K, Takano H, Ohtsuka M, Hasegawa H, Zou Y, Qin Y, Odaka K, Hiroshima K, Tadokoro H, Komuro I (2004) Effects of G-CSF on cardiac remodeling after acute myocardial infarction in swine. Biochem Biophys Res Commun 325:1353–1359PubMedCrossRefGoogle Scholar
  10. 10.
    Harada M, Qin Y, Takano H, Minamino T, Zou Y, Toko H, Ohtsuka M, Matsuura K, Sano M, Nishi J, Iwanaga K, Akazawa H, Kunieda T, Zhu W, Hasegawa H, Kunisada K, Nagai T, Nakaya H, Yamauchi-Takihara K, Komuro I (2005) G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat Med 11:305–311PubMedCrossRefGoogle Scholar
  11. 11.
    Sugano Y, Anzai T, Yoshikawa T, Maekawa Y, Kohno T, Mahara K, Naito K, Ogawa S (2005) Granulocyte colony-stimulating factor attenuates early ventricular expansion after experimental myocardial infarction. Cardiovasc Res 65:446–456PubMedCrossRefGoogle Scholar
  12. 12.
    Takano H, Hasegawa H, Nagai T, Komuro I (2003) Implication of cardiac remodeling in heart failure: mechanisms and therapeutic strategies. Intern Med 42:465–469PubMedCrossRefGoogle Scholar
  13. 13.
    Jugdutt BI (2003) Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough? Circulation 108:1395–1403PubMedCrossRefGoogle Scholar
  14. 14.
    Abbate A, Biondi-Zoccai GG, Baldi A (2002) Pathophysiologic role of myocardial apoptosis in post-infarction left ventricular remodeling. J Cell Physiol 193:145–153PubMedCrossRefGoogle Scholar
  15. 15.
    Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, Anversa P (2001) Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 344:1750–1757PubMedCrossRefGoogle Scholar
  16. 16.
    Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, Pasumarthi KB, Virag JI, Bartelmez SH, Poppa V, Bradford G, Dowell JD, Williams DA, Field LJ (2004) Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428:664–668PubMedCrossRefGoogle Scholar
  17. 17.
    Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC (2004) Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428:668–673PubMedCrossRefGoogle Scholar
  18. 18.
    Kamihata H, Matsubara H, Nishiue T, Fujiyama S, Tsutsumi Y, Ozono R, Masaki H, Mori Y, Iba O, Tateishi E, Kosaki A, Shintani S, Murohara T, Imaizumi T, Iwasaka T (2001) Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 104:1046–1052PubMedCrossRefGoogle Scholar
  19. 19.
    Shintani S, Murohara T, Ikeda H, Ueno T, Honma T, Katoh A, Sasaki K, Shimada T, Oike Y, Imaizumi T (2001) Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 103:2776–2779PubMedCrossRefGoogle Scholar
  20. 20.
    Kajstura J, Rota M, Whang B, Cascapera S, Hosoda T, Bearzi C, Nurzynska D, Kasahara H, Zias E, Bonafe M, Nadal-Ginard B, Torella D, Nascimbene A, Quaini F, Urbanek K, Leri A, Anversa P (2005) Bone marrow cells differentiate in cardiac cell lineages after infarction independently of cell fusion. Circ Res 96:127–137PubMedCrossRefGoogle Scholar
  21. 21.
    Leri A, Kajstura J, Anversa P (2005) Cardiac stem cells and mechanisms of myocardial regeneration. Physiol Rev 85:1373–1416PubMedCrossRefGoogle Scholar
  22. 22.
    Avalos BR (1996) Molecular analysis of the granulocyte colony-stimulating factor receptor. Blood 88:761–777PubMedGoogle Scholar
  23. 23.
    Calhoun DA, Donnelly WH Jr, Du Y, Dame JB, Li Y, Christensen RD (1999) Distribution of granulocyte colony-stimulating factor (G-CSF) and G-CSF-receptor mRNA and protein in the human fetus. Pediatr Res 46:333–338PubMedCrossRefGoogle Scholar
  24. 24.
    Dong F, Larner AC (2000) Activation of Akt kinase by granulocyte colony-stimulating factor (G-CSF): evidence for the role of a tyrosine kinase activity distinct from the Janus kinases. Blood 95:1656–1662PubMedGoogle Scholar
  25. 25.
    Hartung T (1998) Anti-inflammatory effects of granulocyte colony-stimulating factor. Curr Opin Hematol 5:221–225PubMedCrossRefGoogle Scholar
  26. 26.
    Boneberg EM, Hareng L, Gantner F, Wendel A, Hartung T (2000) Human monocytes express functional receptors for granulocyte colony-stimulating factor that mediate suppression of monokines and interferon-gamma. Blood 95:270–276PubMedGoogle Scholar
  27. 27.
    Pajkrt D, Manten A, van der Poll T, Tiel-van Buul MM, Jansen J, Wouter ten Cate J, van Deventer SJ (1997) Modulation of cytokine release and neutrophil function by granulocyte colony-stimulating factor during endotoxemia in humans. Blood 90:1415–1424PubMedGoogle Scholar
  28. 28.
    Bauhofer A, Stinner B, Kohlert F, Reckzeh B, Lorenz W, Celik I (2002) Granulocyte colony-stimulating factor but not peritoneal lavage increases survival rate after experimental abdominal contamination and infection. Br J Surg 89:1457–1464PubMedCrossRefGoogle Scholar
  29. 29.
    Morrison SJ, Uchida N, Weissman IL (1995) The biology of hematopoietic stem cells. Annu Rev Cell Dev Biol 11:35–71PubMedCrossRefGoogle Scholar
  30. 30.
    To LB, Haylock DN, Simmons PJ, Juttner CA (1997) The biology and clinical uses of blood stem cells. Blood 89:2233–2258PubMedGoogle Scholar
  31. 31.
    Link DC (2000) Mechanisms of granulocyte colony-stimulating factor-induced hematopoietic progenitor-cell mobilization. Semin Hematol 37:25–32PubMedCrossRefGoogle Scholar
  32. 32.
    Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S (2001) Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7:430–436PubMedCrossRefGoogle Scholar
  33. 33.
    Wright DE, Bowman EP, Wagers AJ, Butcher EC, Weissman IL (2002) Hematopoietic stem cells are uniquely selective in their migratory response to chemokines. J Exp Med 195:1145–1154Google Scholar
  34. 34.
    Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, Ponomaryov T, Taichman RS, Arenzana-Seisdedos F, Fujii N, Sandbank J, Zipori D, Lapidot T (2002) G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 3:687–694PubMedCrossRefGoogle Scholar
  35. 35.
    Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE, Topol EJ, Penn MS (2003) Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 362:697–703PubMedCrossRefGoogle Scholar
  36. 36.
    Norol F, Merlet P, Isnard R, Sebillon P, Bonnet N, Cailliot C, Carrion C, Ribeiro M, Charlotte F, Pradeau P, Mayol JF, Peinnequin A, Drouet M, Safsafi K, Vernant JP, Herodin F (2003) Influence of mobilized stem cells on myocardial infarct repair in a nonhuman primate model. Blood 102:4361–4368PubMedCrossRefGoogle Scholar
  37. 37.
    Deten A, Volz HC, Clamors S, Leiblein S, Briest W, Marx G, Zimmer HG (2005) Hematopoietic stem cells do not repair the infarcted mouse heart. Cardiovasc Res 65:52–63PubMedCrossRefGoogle Scholar
  38. 38.
    Camici PG (2004) Hibernation and heart failure. Heart 90:141–143PubMedCrossRefGoogle Scholar
  39. 39.
    Heusch G, Schulz R, Rahimtoola SH (2005) Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol 288:H984–H999PubMedCrossRefGoogle Scholar
  40. 40.
    Wijns W, Vatner SF, Camici PG (1998) Hibernating myocardium. N Engl J Med 339:173–181PubMedCrossRefGoogle Scholar
  41. 41.
    Hasegawa H, Takano H, Iwanaga K, Ohtsuka M, Qin Y, Niitsuma Y, Ueda K, Toyoda T, Tadokoro H, Komuro I (2006) Cardioprotective effects of granulocyte colony-stimulating factor in swine with chronic myocardial ischemia. J Am Coll Cardiol (in press)Google Scholar
  42. 42.
    Podewski EK, Hilfiker-Kleiner D, Hilfiker A, Morawietz H, Lichtenberg A, Wollert KC, Drexler H (2003) Alterations in Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling in patients with end-stage dilated cardiomyopathy. Circulation 107:798–802PubMedCrossRefGoogle Scholar
  43. 43.
    Osugi T, Oshima Y, Fujio Y, Funamoto M, Yamashita A, Negoro S, Kunisada K, Izumi M, Nakaoka Y, Hirota H, Okabe M, Yamauchi-Takihara K, Kawase I, Kishimoto T (2002) Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart. J Biol Chem 277:6676–6681PubMedCrossRefGoogle Scholar
  44. 44.
    Oshima Y, Fujio Y, Nakanishi T, Itoh N, Yamamoto Y, Negoro S, Tanaka K, Kishimoto T, Kawase I, Azuma J (2005) STAT3 mediates cardioprotection against ischemia/reperfusion injury through metallothionein induction in the heart. Cardiovasc Res 65:428–435PubMedCrossRefGoogle Scholar
  45. 45.
    Wallace KB (2003) Doxorubicin-induced cardiac mitochondrionopathy. Pharmacol Toxicol 93:105–115PubMedCrossRefGoogle Scholar
  46. 46.
    Kunisada K, Negoro S, Tone E, Funamoto M, Osugi T, Yamada S, Okabe M, Kishimoto T, Yamauchi-Takihara K (2000) Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy. Proc Natl Acad Sci USA 97:315–319PubMedCrossRefGoogle Scholar
  47. 47.
    Zou Y, Takano H, Mizukami M, Akazawa H, Qin Y, Toko H, Sakamoto M, Minamino T, Nagai T, Komuro I (2003) Leukemia inhibitory factor enhances survival of cardiomyocytes and induces regeneration of myocardium after myocardial infarction. Circulation 108:748–753PubMedCrossRefGoogle Scholar
  48. 48.
    Kang HJ, Kim HS, Zhang SY, Park KW, Cho HJ, Koo BK, Kim YJ, Soo Lee D, Sohn DW, Han KS, Oh BH, Lee MM, Park YB (2004) Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet 363:751–756PubMedCrossRefGoogle Scholar
  49. 49.
    Kong D, Melo LG, Gnecchi M, Zhang L, Mostoslavsky G, Liew CC, Pratt RE, Dzau VJ (2004) Cytokine-induced mobilization of circulating endothelial progenitor cells enhances repair of injured arteries. Circulation 110:2039–2046PubMedCrossRefGoogle Scholar
  50. 50.
    Valgimigli M, Rigolin GM, Cittanti C, Malagutti P, Curello S, Percoco G, Bugli AM, Porta MD, Bragotti LZ, Ansani L, Mauro E, Lanfranchi A, Giganti M, Feggi L, Castoldi G, Ferrari R (2005) Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile. Eur Heart J 26:1838–1845PubMedCrossRefGoogle Scholar
  51. 51.
    Kuethe F, Figulla HR, Herzau M, Voth M, Fritzenwanger M, Opfermann T, Pachmann K, Krack A, Sayer HG, Gottschild D, Werner GS (2005) Treatment with granulocyte colony-stimulating factor for mobilization of bone marrow cells in patients with acute myocardial infarction. Am Heart J 150:115 (e1–7)PubMedCrossRefGoogle Scholar
  52. 52.
    Jorgensen E, Ripa RS, Helqvist S, Wang Y, Johnsen HE, Grande P, Kastrup J (2006) In-stent neo-intimal hyperplasia after stem cell mobilization by granulocyte-colony stimulating factor preliminary intracoronary ultrasound results from a double-blind randomized placebo-controlled study of patients treated with percutaneous coronary intervention for ST-elevation myocardial infarction (STEMMI Trial). Int J Cardiol (in press)Google Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Hiroyuki Takano
    • 1
  • Yingjie Qin
    • 1
  • Hiroshi Hasegawa
    • 1
  • Kazutaka Ueda
    • 1
  • Yuriko Niitsuma
    • 1
  • Masashi Ohtsuka
    • 1
  • Issei Komuro
    • 1
  1. 1.Department of Cardiovascular Science and MedicineChiba University Graduate School of MedicineChibaJapan

Personalised recommendations