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. 2016 Jun 9;13(3):297–303. doi: 10.1007/s13770-016-9054-9

Local injection of granulocyte-colony stimulating factor accelerates wound healing in a rat excisional wound model

Guang-Yin Shen 1, In-Hwa Park 2, Yi-Sun Song 2, Hyun-Woo Joo 2, Yonggu Lee 1, Jeong-Hun Shin 1, Kyung-Soo Kim 1,2, Hyuck Kim 3,
PMCID: PMC6170830  PMID: 30603411

Abstract

A systemic treatment of granulocyte-colony stimulating factor (G-CSF) is known to improve healings of damaged tissues. However, recent studies suggested local actions of G-CSF on the healing processes of damaged tissues. We investigated the treatment effect of locally injected G-CSF and compared to that of systemically injected G-CSF in a rat model. A wound was created on the rat dorsum and treated either by local injection or by systemic injection of G-CSF. Wound healing rate, deposition of collagen, and gene expression were evaluated. G-CSF receptor (G-CSFR) protein was detected by Western blotting. The wound healing rate in the local injection group was significantly higher than that in the systemic injection group at days 9 and 15; it was also significantly higher than that in the control group at days 3, 9, and 15. The expression of G-CSFR protein in wound tissues was higher than in normal skin tissues. The local injection of G-CSF is more effective than systemic injection of G-CSF in promoting wound healing, which may implicate the local action of G-CSF treatment in wound healing processes.

Keywords: Granulocyte-colony stimulating factor, Wound healing, Local injection

Footnotes

These authors contributed equally to this work.

References

  • 1.Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med. 1999;341:738–746. doi: 10.1056/NEJM199909023411006. [DOI] [PubMed] [Google Scholar]
  • 2.Nie C, Yang D, Xu J, Si Z, Jin X, Zhang J. Locally administered adiposederived stem cells accelerate wound healing through differentiation and vasculogenesis. Cell Transplant. 2011;20:205–216. doi: 10.3727/096368910X520065. [DOI] [PubMed] [Google Scholar]
  • 3.Reddy JS, Rao PR, Reddy MS. Wound healing effects of Heliotropium indicum, Plumbago zeylanicum and Acalypha indica in rats. J Ethnopharmacol. 2002;79:249–251. doi: 10.1016/S0378-8741(01)00388-9. [DOI] [PubMed] [Google Scholar]
  • 4.Panopoulos AD, Watowich SS. Granulocyte colony-stimulating factor: molecular mechanisms of action during steady state and ‘emergency’ hematopoiesis. Cytokine. 2008;42:277–288. doi: 10.1016/j.cyto.2008.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Minatoguchi S, Takemura G, Chen XH, Wang N, Uno Y, Koda M, et al. 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. 2004;109:2572–2580. doi: 10.1161/01.CIR.0000129770.93985.3E. [DOI] [PubMed] [Google Scholar]
  • 6.Wang Y, Sun Y, Yang XY, Ji SZ, Han S, Xia ZF. Mobilised bone marrowderived cells accelerate wound healing. Int Wound J. 2013;10:473–479. doi: 10.1111/j.1742-481X.2012.01007.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Harada M, Qin Y, Takano H, Minamino T, Zou Y, Toko H, et al. G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat Med. 2005;11:305–311. doi: 10.1038/nm1199. [DOI] [PubMed] [Google Scholar]
  • 8.Li L, Takemura G, Li Y, Miyata S, Esaki M, Okada H, et al. Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy. Lab Invest. 2007;87:440–455. doi: 10.1038/labinvest.3700516. [DOI] [PubMed] [Google Scholar]
  • 9.Boneberg EM, Hartung T. Molecular aspects of anti-inflammatory action of G-CSF. Inflamm Res. 2002;51:119–128. doi: 10.1007/PL00000283. [DOI] [PubMed] [Google Scholar]
  • 10.Mueller MM, Fusenig NE. Constitutive expression of G-CSF and GMCSF in human skin carcinoma cells with functional consequence for tumor progression. Int J Cancer. 1999;83:780–789. doi: 10.1002/(SICI)1097-0215(19991210)83:6<780::AID-IJC14>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
  • 11.Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. J Pharmacol Pharmacother. 2010;1:94–99. doi: 10.4103/0976-500X.72351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Morton JJ, Malone MH. Evaluation of vulneray activity by an open wound procedure in rats. Arch Int Pharmacodyn Ther. 1972;196:117–126. [PubMed] [Google Scholar]
  • 13.Fang Y, Gong SJ, Xu YH, Hambly BD, Bao S. Impaired cutaneous wound healing in granulocyte/macrophage colony-stimulating factor knockout mice. Br J Dermatol. 2007;157:458–465. doi: 10.1111/j.1365-2133.2007.07979.x. [DOI] [PubMed] [Google Scholar]
  • 14.Walker HL, Mason AD., Jr A standard animal burn. J Trauma. 1968;8:1049–1051. doi: 10.1097/00005373-196811000-00006. [DOI] [PubMed] [Google Scholar]
  • 15.Song YS, Fang CH, So BI, Park JY, Jun DW, Kim KS. Therapeutic effects of granulocyte-colony stimulating factor on non-alcoholic hepatic steatosis in the rat. Ann Hepatol. 2013;12:115–122. [PubMed] [Google Scholar]
  • 16.Song YS, Fang CH, So BI, Park JY, Lee Y, Shin JH, et al. Time course of the development of nonalcoholic Fatty liver disease in the Otsuka longevans Tokushima Fatty rat. Gastroenterol Res Pract. 2013;2013:342648. doi: 10.1155/2013/342648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Kim YS, Cho IH, Jeong MJ, Jeong SJ, Nah SY, Cho YS, et al. Therapeutic effect of total ginseng saponin on skin wound healing. J Ginseng Res. 2011;35:360–367. doi: 10.5142/jgr.2011.35.3.360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Fukuhara S, Tomita S, Nakatani T, Ohtsu Y, Ishida M, Yutani C, et al. GCSF promotes bone marrow cells to migrate into infarcted mice heart, and differentiate into cardiomyocytes. Cell Transplant. 2004;13:741–748. doi: 10.3727/000000004783983486. [DOI] [PubMed] [Google Scholar]
  • 19.Yang Y, Zhang W, Li Y, Fang G, Zhang K. Scalded skin of rat treated by using fibrin glue combined with allogeneic bone marrow mesenchymal stem cells. Ann Dermatol. 2014;26:289–295. doi: 10.5021/ad.2014.26.3.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Frank T, Schlachetzki JC, Göricke B, Meuer K, Rohde G, Dietz GP, et al. Both systemic and local application of granulocyte-colony stimulating factor (G-CSF) is neuroprotective after retinal ganglion cell axotomy. BMC Neurosci. 2009;10:49. doi: 10.1186/1471-2202-10-49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med. 2011;13:e23. doi: 10.1017/S1462399411001943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol. 2007;127:514–525. doi: 10.1038/sj.jid.5700701. [DOI] [PubMed] [Google Scholar]
  • 23.Chithra P, Sajithlal GB, Chandrakasan G. Influence of Aloe vera on collagen characteristics in healing dermal wounds in rats. Mol Cell Biochem. 1998;181:71–76. doi: 10.1023/A:1006813510959. [DOI] [PubMed] [Google Scholar]
  • 24.Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453:314–321. doi: 10.1038/nature07039. [DOI] [PubMed] [Google Scholar]
  • 25.Barrientos S, Brem H, Stojadinovic O, Tomic-Canic M. Clinical application of growth factors and cytokines in wound healing. Wound Repair Regen. 2014;22:569–578. doi: 10.1111/wrr.12205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Mustoe TA, Pierce GF, Morishima C, Deuel TF. Growth factor-induced acceleration of tissue repair through direct and inductive activities in a rabbit dermal ulcer model. J Clin Invest. 1991;87:694–703. doi: 10.1172/JCI115048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Tsang MW, Wong WK, Hung CS, Lai KM, Tang W, Cheung EY, et al. Human epidermal growth factor enhances healing of diabetic foot ulcers. Diabetes Care. 2003;26:1856–1861. doi: 10.2337/diacare.26.6.1856. [DOI] [PubMed] [Google Scholar]
  • 28.Nissen NN, Polverini PJ, Koch AE, Volin MV, Gamelli RL, DiPietro LA. Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. Am J Pathol. 1998;152:1445–1452. [PMC free article] [PubMed] [Google Scholar]
  • 29.Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP, Brem H. The role of vascular endothelial growth factor in wound healing. J Surg Res. 2009;153:347–358. doi: 10.1016/j.jss.2008.04.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Iwamoto S, Lin X, Ramirez R, Carson P, Fiore D, Goodrich J, et al. Bone marrow cell mobilization by the systemic use of granulocyte colony-stimulating factor (GCSF) improves wound bed preparation. Int J Low Extrem Wounds. 2013;12:256–264. doi: 10.1177/1534734613513401. [DOI] [PubMed] [Google Scholar]
  • 31.Iwanaga K, Takano H, Ohtsuka M, Hasegawa H, Zou Y, Qin Y, et al. Effects of G-CSF on cardiac remodeling after acute myocardial infarction in swine. Biochem Biophys Res Commun. 2004;325:1353–1359. doi: 10.1016/j.bbrc.2004.10.149. [DOI] [PubMed] [Google Scholar]
  • 32.Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, et al. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci U S A. 2009;106:6742–6747. doi: 10.1073/pnas.0902280106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Zaruba MM, Theiss HD, Vallaster M, Mehl U, Brunner S, David R, et al. Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell. 2009;4:313–323. doi: 10.1016/j.stem.2009.02.013. [DOI] [PubMed] [Google Scholar]

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