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Additive effect of endothelial progenitor cell mobilization and bone marrow mononuclear cell transplantation on angiogenesis in mouse ischemic limbs

  • Published:
Journal of Biomedical Science

Summary

The methods of therapeutic angiogenesis include endothelial progenitor cell (EPC) mobilization with cytokines [e.g., granulocyte colony-stimulating factor (G-CSF)] and bone marrow mononuclear cell (BMMNC) transplantation. Combined angiogenic therapies may be superior to a single angiogenic therapy for the treatment of limb ischemia. Therefore, we investigated whether the angiogenic efficacy of a combination of two angiogenic strategies is superior to either strategy alone. One day after the surgical induction of hindlimb ischemia, mice were randomized to receive either no treatment, EPC mobilization with G-CSF administration, BMMNC transplantation using a fibrin matrix, or a combination of EPC mobilization with BMMNC transplantation using a fibrin matrix. EPC mobilization with G-CSF or BMMNC transplantation using a fibrin matrix significantly increased the microvessel density compared with no treatment. Importantly, a combination of EPC mobilization with BMMNC transplantation using a fibrin matrix further increased the densities of microvessels and BrdU-positive capillaries compared to either strategy alone. Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) expression was higher in the EPC mobilization with G-CSF or BMMNC transplantation group than in the no treatment group. The combination therapy of EPC mobilization with G-CSF and BMMNC transplantation resulted in more extensive expression of bFGF and VEGF than the single therapy of either EPC mobilization with G-CSF treatment or BMMNC transplantation. This study demonstrates that the combination therapy of BMMNC transplantation and EPC mobilization potentiates the angiogenic efficacy of either single therapy in mouse limb ischemia models.

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References

  1. Iwakura A., Luedemann C., Shastry S., Hanley A., Kearney M., Aikawa R., Isner J.M., Asahara T., Losordo D.W. (2003) Estrogen-mediated, endothelial nitric oxide synthase–dependent mobilization of bone marrow–derived endothelial progenitor cells contributes to reendothelialization after arterial injury. Circulation 108:3115–3121

    Article  PubMed  CAS  Google Scholar 

  2. Kocher A.A., Schuster M.D., Szabolcs M.J., Takuma S., Burkhoff D., Wang J., Homma S., Edwards N.M., Itescu S. (2001) Neovascularization of ischemic myocardium by human bone marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat. Med. 7:430–436

    Article  PubMed  CAS  Google Scholar 

  3. Jeon O., Hwang K.C., Yoo K.J., Kim B.S. (2006) Combined sustained delivery of basic fibroblast growth factor and administration of granulocyte colony-stimulating factor: synergistic effect on angiogenesis in mouse ischemic limbs. J. Endovasc. Ther. 13:175–181

    Article  PubMed  Google Scholar 

  4. Hamano K., Li T.S., Kobayashi T., Kobayashi S., Matsuzaki M., Esato K. (2000) Angiogenesis induced by the implantation of self-bone marrow cells: a new material for therapeutic angiogenesis. Cell Transplant. 9:439–443

    PubMed  CAS  Google Scholar 

  5. 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 104:1046–1052

    PubMed  CAS  Google Scholar 

  6. Orlic D., Kajstura J., Chimenti S., Jakoniuk I., Anderson S.M., Li B., Pickel J., McKay R., Nadal-Ginard B., Bodine D.M., Leri A., Anversa P. (2001) Bone marrow cells regenerate infarcted myocardium. Nature 5410:701–705

    Article  Google Scholar 

  7. Strauer B.E., Brehm M., Zeus T., Kostering M., Hernandez A., Sorg R.V., Kogler G., Wernet P. (2002) Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106:1913–1918

    Article  PubMed  Google Scholar 

  8. Jeon O., Kang S.W., Lim H.W., Choi D., Kim D.I., Lee S.H., Chung J.H., Kim B.S. (2006) Synergistic effect of sustained delivery of basic fibroblast growth factor and bone marrow mononuclear cell transplantation on angiogenesis in mouse ischemic limbs. Biomaterials 27:1617–1625

    Article  PubMed  CAS  Google Scholar 

  9. Ferrara N., Alitalo K. (1999) Clinical application of angiogenic growth factors and their inhibitors. Nat. Med. 5: 1359–1364

    Article  PubMed  CAS  Google Scholar 

  10. Jeon O., Kang S.W., Lim H.W., Chung J.H., Kim B.S. (2006) Long-term and zero-order release of basic fibroblast growth factor from heparin-conjugated poly(L-lactide-co-glycolide) nanospheres and fibrin gel. Biomaterials 27:1598–1607

    Article  PubMed  CAS  Google Scholar 

  11. Jeon O., Ryu S.H., Chung J.H., Kim B.S. (2005) Control of basic fibroblast growth factor release from fibrin gel with heparin and concentrations of fibrinogen and thrombin. J. Control. Release 105:249–259

    Article  PubMed  CAS  Google Scholar 

  12. Hematti P., Sellers S.E., Agricola B.A., Metzger M.E., Donahue R.E., Dunbar C.E. (2003) Retroviral transduction efficiency of G-CSF + SCF-mobilized peripheral blood CD34 + cells is superior to G-CSF or G-CSF + Flt3-L-mobilized cells in nonhuman primates. Blood 101:2199–2205

    Article  PubMed  CAS  Google Scholar 

  13. Prosper F., Sola C., Hornedo J., Arbona C., Menendez P., Orfao A., Lluch A., Cortes-Funes H., Lopez J.J., Garcia-Conde J. (2003) Mobilization of peripheral blood progenitor cells with a combination of cyclophosphamide, r-metHuSCF and filgrastim in patients with breast cancer previously treated with chemotherapy. Leukemia 17:437–441

    Article  PubMed  CAS  Google Scholar 

  14. Wadhwa P.D., Lazarus H.M., Koc O.N., Jaroscak J., Woo D., Stevens C.E., Rubinstein P., Laughlin M.J. (2003) Hematopoietic recovery after unrelated umbilical cord-blood allogeneic transplantation in adults treated with in vivo stem cell factor (R-MetHuSCF) and filgrastim administration Leuk. Res. 27:215–220

    Article  PubMed  CAS  Google Scholar 

  15. Cho S.W., Kim I.K., Lim S.H., Kim D.I., Kang S.W., Kim S.H., Kim Y.H., Lee E.Y., Choi C.Y., Kim B.S. (2004) Smooth muscle-like tissues engineering with bone marrow stromal cells. Biomaterials 25:2979–2986

    Article  PubMed  CAS  Google Scholar 

  16. Couffinhal T., Silver M., Zheng L.P., Kearney M., Witzenbichler B., Isner J.M. (1998) Mouse model of angiogenesis. Am. J. Pathol. 152:1667–1679

    PubMed  CAS  Google Scholar 

  17. Powell T.M., Paul J.D., Hill J.M., Thompson M., Benjamin M., Rodrigo M., McCoy J.P., Read E.J., Khuu H.M., Leitman S.F., Finkel T., Cannon III R.O. (2005) Granulocyte colony-stimulating factor mobilizes functional endothelial progenitor cells in patients with coronary artery disease. Arterioscler, Thromb. Vasc. Biol. 25:296–301

    Article  CAS  Google Scholar 

  18. Peled A., Petit I., Kollet O., Magid M., Ponomaryov T., Byk T., Nagler A., Ben-Hur H., Many A., Shultz L., Lider O., Alon R., Zipori D., Lapidot T. (1999) Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283:845–848

    Article  PubMed  CAS  Google Scholar 

  19. Reyes M., Dudek A., Jahagirdar B., Koodie L., Marker P.H., Verfaillie C.M. (2002) Origin of endothelial progenitors in human postnatal bone marrow. J. Clin. Invest. 109:337–346

    Article  PubMed  CAS  Google Scholar 

  20. Bauters C., Asahara T., Zheng L.P., Takeshita S., Bunting S., Ferrara N., Symes J.F., Isner J.M. (1995) Recovery of disturbed endothelium-dependent flow in the collateral-perfused rabbit ischemic hindlimb after administration of vascular endothelial growth factor. Circulation 91:2802–2809

    PubMed  CAS  Google Scholar 

  21. Shen B.-Q., Lee D.Y., Zioncheck T.Z. (1999) Vascular endothelial growth factor governs endothelial nitric-oxide synthase expression via a KDR/FLK-1 receptor and a protein kinase C signaling pathway. J. Biol. Chem. 274:33057–33063

    Article  PubMed  CAS  Google Scholar 

  22. Shintani S., Murohara T., Ikeda H., Ueno T., Sasaki K., Duan J., Imaizumi T. (2001) Augmentation of postnatal neovascularization with autologous bone marrow transplantation. Circulation 103:897–903

    PubMed  CAS  Google Scholar 

  23. Bretland A.J., Lawry J., Sharrard R.M. (2001) A study of death by anoikis in cultured epithelial cells. Cell Prolif. 34:199–210

    Article  PubMed  CAS  Google Scholar 

  24. Folkman J. (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1:27–30

    Article  PubMed  CAS  Google Scholar 

  25. Kornowski R., Baim D.S., Moses J.W., Hong M.K., Laham R.J., Fuchs S., Hendel R.C., Wallace D., Cohen D.J., Bonow R.O., Kuntz R.E., Leon M.B. (2000) Short- and intermediate-term clinical outcomes from direct myocardial laser revascularization guided by biosense left ventricular electromechanical mapping. Circulation 102:1120–1125

    PubMed  CAS  Google Scholar 

  26. Simons M., Annex B.H., Laham R.J., Kleiman N., Henry T., Dauerman H., Udelson J.E., Gervino E.V., Pike M., Whitehouse M.J., Moon T., Chronos N.A. (2002) Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation 105:788–793

    Article  PubMed  CAS  Google Scholar 

  27. Bussolino F., Ziche M., Wang J.M., Alessi D., Morbidelli L., Cremona O., Bosia A., Marchisio P.C., Mantovani A. (1991) In vitro and in vivo activation of endothelial cells by colony-stimulating factors. J. Clin. Invest. 87:986–995

    Article  PubMed  CAS  Google Scholar 

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Acknowledgement

This work was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (grant no. A050082).

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Authors and Affiliations

  1. Department of Chemical Engineering, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul, 133-791, Korea

    Oju Jeon, Su Jin Song & Suk Ho Bhang

  2. Department of Bioengineering, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul, 133-791, Korea

    Byung-Soo Kim

  3. School of Chemical and Biological Engineering, Seoul National University, Seoul, Korea

    Suk Ho Bhang & Cha-Yong Choi

  4. Department of Laboratory, Medicine Asan Institute for Life Sciences College of Medicine, University of Ulsan, Seoul, 138-736, Korea

    Mi Jung Kim

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  1. Oju Jeon
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Correspondence to Byung-Soo Kim.

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Jeon, O., Song, S.J., Bhang, S.H. et al. Additive effect of endothelial progenitor cell mobilization and bone marrow mononuclear cell transplantation on angiogenesis in mouse ischemic limbs. J Biomed Sci 14, 323–330 (2007). https://doi.org/10.1007/s11373-007-9145-7

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  • DOI: https://doi.org/10.1007/s11373-007-9145-7

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