Cardiovascular Drugs and Therapy

, Volume 22, Issue 5, pp 363–371 | Cite as

Mobilization of Mesenchymal Stem Cells by Granulocyte Colony-stimulating Factor in Rats with Acute Myocardial Infarction

  • Zhaokang Cheng
  • Xiaolei Liu
  • Lailiang Ou
  • Xin Zhou
  • Yi Liu
  • Xiaohua Jia
  • Jin Zhang
  • Yuming Li
  • Deling Kong



Intravenous delivery of mesenchymal stem cells (MSCs), a noninvasive strategy for myocardial repair after acute myocardial infarction (MI), is limited by the low percentage of MSCs migration to the heart. The purpose of this study was to test whether granulocyte colony-stimulating factor (G-CSF) would enhance the colonization of intravenously infused MSCs in damaged heart in a rat model of acute MI.


After induction of anterior MI, Sprague–Dawley rats were randomized to receive: (1) saline (n = 9); (2) MSCs (n = 15); and (3) MSCs plus G-CSF (50 μg/kg/day for 5 consecutive days, n = 13).


Flow cytometry revealed that G-CSF slightly increased surface CXCR4 expression on MSCs in vitro. After completion of G-CSF administration, MSCs showed a significantly lower colonization in bone marrow and a trend toward higher localization in the infarcted myocardium. At 3 months, vessel density in the infarct region of heart was significantly increased in MSCs group and trended to increase in MSCs + G-CSF group. However, echocardiographic and hemodynamic parameters, including left ventricular (LV) end-diastolic diameters, ejection fraction, and ±dP/dt max, were not statistically different. Morphological analysis showed that infarct size and collagen content were similar in the three groups. Immunohistochemistry revealed that the combined therapy accelerated endothelial recovery of the blood vessels in the ischemic myocardium. However, myocardial regeneration resulting from MSCs differentiation was not observed.


G-CSF enhanced the migration of systemically delivered MSCs from bone marrow to infarcted heart. However, the beneficial effect of this kind of migration is limited, as cardiac function did not improve.

Key words

Mesenchymal stem cells G-CSF Migration Myocardial infarction 



This work is supported by grants from Natural Science Foundation of Tianjin (05YFJZJC01601 to L.O.) and Natural Science Foundation of China (30570471, 30725030 to D.K., 30500645 to J.Z.).


  1. 1.
    Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Kawada H, Fujita J, Kinjo K, et al. Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood 2004;104:3581–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Silva GV, Litovsky S, Assad JAR, et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation 2005;111:150–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Mangi AA, Noiseux N, Kong D, et al. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 2003;9:1195–201.PubMedCrossRefGoogle Scholar
  5. 5.
    Noiseux N, Gnecchi M, Lopez-Ilasaca M, et al. Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther 2006;14:840–50.PubMedCrossRefGoogle Scholar
  6. 6.
    Cheng Z, Ou L, Zhou X, et al. Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance. Mol Ther 2008;16:571–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Devine SM, Bartholomew AM, Mahmud N, et al. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp Hematol 2001;29:244–55.PubMedCrossRefGoogle Scholar
  8. 8.
    Barbash IM, Chouraqui P, Baron J, et al. Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation 2003;108:863–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Petit I, Szyper-Kravitz M, Nagler A, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 2002;3:687–94.PubMedCrossRefGoogle Scholar
  10. 10.
    Levesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest 2003;111:187–96.PubMedGoogle Scholar
  11. 11.
    Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 2001;98:10344–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Cho SW, Gwak SJ, Kim IK, et al. Granulocyte colony-stimulating factor treatment enhances the efficacy of cellular cardiomyoplasty with transplantation of embryonic stem cell-derived cardiomyocytes in infarcted myocardium. Biochem Biophys Res Commun 2006;340:573–82.PubMedCrossRefGoogle Scholar
  13. 13.
    Kong D, Melo LG, Gnecchi M, et al. Cytokine-induced mobilization of circulating endothelial progenitor cells enhances repair of injured arteries. Circulation 2004;110:2039–46.PubMedCrossRefGoogle Scholar
  14. 14.
    Nagaya N, Fujii T, Iwase T, et al. Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis. Am J Physiol Heart Circ Physiol 2004;287:H2670–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Jiang W, Ma A, Wang T, et al. Homing and differentiation of mesenchymal stem cells delivered intravenously to ischemic myocardium in vivo: a time-series study. Pflugers Arch 2006;453:43–52.PubMedCrossRefGoogle Scholar
  16. 16.
    Price MJ, Chou CC, Frantzen M, et al. Intravenous mesenchymal stem cell therapy early after reperfused acute myocardial infarction improves left ventricular function and alters electrophysiologic properties. Int J Cardiol 2006;111:231–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Boomsma RA, Swaminathan PD, Geenen DL. Intravenously injected mesenchymal stem cells home to viable myocardium after coronary occlusion and preserve systolic function without altering infarct size. Int J Cardiol 2007;122:17–28.PubMedCrossRefGoogle Scholar
  18. 18.
    Shyu WC, Lin SZ, Yang HI, et al. Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation 2004;110:1847–54.PubMedCrossRefGoogle Scholar
  19. 19.
    Adachi Y, Imagawa J, Suzuki Y, et al. G-CSF treatment increases side population cell infiltration after myocardial infarction in mice. J Mol Cell Cardiol 2004;36:707–10.PubMedCrossRefGoogle Scholar
  20. 20.
    Fukuhara S, Tomita S, Nakatani T, et al. G-CSF promotes bone marrow cells to migrate into infarcted mice heart, and differentiate into cardiomyocytes. Cell Transplant 2004;13:741–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Misao Y, Takemura G, Arai M, et al. Importance of recruitment of bone marrow-derived CXCR4+ cells in post-infarct cardiac repair mediated by G-CSF. Cardiovasc Res 2006;71:455–65.PubMedCrossRefGoogle Scholar
  22. 22.
    Wynn RF, Hart CA, Corradi-Perini C, et al. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood 2004;104:2643–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Wu Y, Ip JE, Huang J, et al. Essential role of ICAM-1/CD18 in mediating EPC recruitment, angiogenesis, and repair to the infarcted myocardium. Circ Res 2006;99:315–22.PubMedCrossRefGoogle Scholar
  24. 24.
    Deindl E, Zaruba MM, Brunner S, et al. G-CSF administration after myocardial infarction in mice attenuates late ischemic cardiomyopathy by enhanced arteriogenesis. FASEB J 2006;20:956–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Harada M, Qin Y, Takano H, et al. G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat Med 2005;11:305–11.PubMedCrossRefGoogle Scholar
  26. 26.
    Cho HJ, Kim TY, Cho HJ, et al. The effect of stem cell mobilization by granulocyte-colony stimulating factor on neointimal hyperplasia and endothelial healing after vascular injury with bare-metal versus paclitaxel-eluting stents. J Am Coll Cardiol 2006;48:366–74.PubMedCrossRefGoogle Scholar
  27. 27.
    Tateishi-Yuyama E, Matsubara H, Murohara T, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 2002;360:427–35.PubMedCrossRefGoogle Scholar
  28. 28.
    Takakura N, Watanabe T, Suenobu S, et al. A role for hematopoietic stem cells in promoting angiogenesis. Cell 2000;102:199–209.PubMedCrossRefGoogle Scholar
  29. 29.
    Kinnaird T, Stabile E, Burnett MS, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res 2004;94:678–85.PubMedCrossRefGoogle Scholar
  30. 30.
    Ohki Y, Heissig B, Sato Y, et al. Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils. FASEB J 2005;19:2005–7.PubMedGoogle Scholar
  31. 31.
    Hoefer IE, Grundmann S, van Royen N, et al. Leukocyte subpopulations and arteriogenesis: Specific role of monocytes, lymphocytes and granulocytes. J Am Coll Cardiol 2005;181:285–9.Google Scholar
  32. 32.
    Bussolino F, Wang JM, Defilippi P, et al. Granulocyte- and granulocyte-macrophage-colony stimulating factors induce human endothelial cells to migrate and proliferate. Nature 1989;337:471–3.PubMedCrossRefGoogle Scholar
  33. 33.
    Werneck-de-Castro JP, Costa-E-Sousa RH, de Oliveira PF, et al. G-CSF does not improve systolic function in a rat model of acute myocardial infarction. Basic Res Cardiol 2006;101:494–501.PubMedCrossRefGoogle Scholar
  34. 34.
    Deten A, Volz HC, Clamors S, et al. Hematopoietic stem cells do not repair the infarcted mouse heart. Cardiovasc Res 2005;65:52–63.PubMedCrossRefGoogle Scholar
  35. 35.
    Hill JM, Syed MA, Arai AE, et al. Outcomes and risks of granulocyte colony-stimulating factor in patients with coronary artery disease. J Am Coll Cardiol 2005;46:1643–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Kang HJ, Kim HS, Zhang SY, et al. 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 2004;363:751–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Zohlnhofer D, Ott I, Mehilli J, et al. Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA 2006;295:1003–10.PubMedCrossRefGoogle Scholar
  38. 38.
    Ripa RS, Jorgensen E, Wang Y, et al. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial. Circulation 2006;113:1983–92.PubMedCrossRefGoogle Scholar
  39. 39.
    Engelmann MG, Theiss HD, Hennig-Theiss C, et al. Autologous bone marrow stem cell mobilization induced by granulocyte colony-stimulating factor after subacute ST-segment elevation myocardial infarction undergoing late revascularization: final results from the G-CSF-STEMI (Granulocyte Colony-Stimulating Factor ST-Segment Elevation Myocardial Infarction) trial. J Am Coll Cardiol 2006;48:1712–21.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Zhaokang Cheng
    • 1
  • Xiaolei Liu
    • 1
  • Lailiang Ou
    • 1
  • Xin Zhou
    • 2
  • Yi Liu
    • 1
  • Xiaohua Jia
    • 1
  • Jin Zhang
    • 3
  • Yuming Li
    • 2
  • Deling Kong
    • 1
  1. 1.Key Laboratory of Bioactive Materials of Education of Ministry, College of Life ScienceNankai UniversityTianjinChina
  2. 2.Institute of Cardiovascular Disease, Pingjin HospitalMedical College of Chinese People’s Armed Police ForcesTianjinChina
  3. 3.Department of AnatomyGuangzhou University of Traditional Chinese MedicineGuangzhouChina

Personalised recommendations