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Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization

Abstract

Endothelial progenitor cells (EPCs) have been isolated from circulating mononuclear cells in human peripheral blood and shown to be incorporated into foci of neovascularization, consistent with postnatal vasculogenesis1. We determined whether endogenous stimuli (tissue ischemia) and exogenous cytokine therapy (granulocyte macrophage-colony stimulating factor, GM-CSF) mobilize EPCs and thereby contribute to neovascularization of ischemic tissues. The development of regional ischemia in both mice and rabbits increased the frequency of circulating EPCs. In mice, the effect of ischemia-induced EPC mobilization was demonstrated by enhanced ocular neovascularization after cornea micropocket surgery in mice with hindlimb ischemia compared with that in non-ischemic control mice. In rabbits with hindlimb ischemia, circulating EPCs were further augmented after pretreatment with GM-CSF, with a corresponding improvement in hindlimb neovascularization. There was direct evidence that EPCs that contributed to enhanced corneal neovascularization were specifically mobilized from the bone marrow in response to ischemia and GM-CSF in mice transplanted with bone marrow from transgenic donors expressing β-galactosidase transcriptionally regulated by the endothelial cell-specific Tie-2 promoter. These findings indicate that circulating EPCs are mobilized endogenously in response to tissue ischemia or exogenously by cytokine therapy and thereby augment neovascularization of ischemic tissues.

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Figure 1: EPCs derived from isolated populations of Sca-1+ cells in mice and TBM cells in rabbit can 'home' and incorporate into foci of neovascularization.
Figure 2: EPC kinetics in relation to the development of hindlimb ischemia.
Figure 3: Effect of GM-CSF-induced EPC mobilization on neovascularization in rab-bit ischemic hindlimb model and mouse corneal neovascular-ization model.
Figure 4: Bone marrow-derived EPCs contribute to corneal neovascularization.

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References

  1. Asahara, T. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 965–967 (1997).

    Article  Google Scholar 

  2. Couffinhal, T. et al. A mouse model of angiogenesis. Am. J. Pathol. 152, 1667–1679 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Takeshita, S. et al. Therapeutic angiogenesis: A single intra-arterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hindlimb model. J. Clin. Invest. 93, 662–670 (1994).

    Article  CAS  Google Scholar 

  4. Ledney, G.D. et al. Hematopoietic colony-forming cells from mice after wound trauma. J. Surg. Res. 38, 55–65 (1985).

    Article  CAS  Google Scholar 

  5. Socinksi, M., Cannistra, S., Elias, A., Antman, K., Schnipper, L. & Griffin, J. Granulocyte-macrophage colony stimulating factor expands the circulating haematopoietic progenitor cell compartment in man. Lancet 1, 1194–1198 (1988).

    Google Scholar 

  6. Clark, S. & Kamen, R. The human hematopoietic colony stimulating factors. Science 236, 1229– 1237 (1987).

    Article  CAS  Google Scholar 

  7. Dedhar, S., Batoury, L., Galloway, P. & Eaves, C. Human granulocyte-macrophage colony-stimulating factor is a growth factor active on a variety of cell types of non-hemopoietic origin. Proc. Natl. Acad. Sci. USA 85, 9253–9257 (1988).

    Article  CAS  Google Scholar 

  8. Bussolino, F. et al. Granulocyte- granulocyte-macrophage-colony stimulating factors induce human endothelial cells to migrate and proliferate. Nature 337, 471–473 ( 1989).

    Article  CAS  Google Scholar 

  9. Bussolino, F. et al. In vitro and in vivo activation of endothelial cells by colony-stimulating factors. J. Clin. Invest. 87, 986–995 (1991).

    Article  CAS  Google Scholar 

  10. Soldi, R. et al. Activation of JAK2 in human vascular endothelial cells by granulocyte-macrophage colony-stimulating factor. Blood 89, 863 –872 (1997).

    CAS  PubMed  Google Scholar 

  11. Bussolino, F. et al. Stimulation of the Na+/H+ exchanger in human endothelial cells activated by granulocyte- and granulocyte-macrophage-colony stimulating factor. Evidence for a role in proliferation and migration. J. Biol. Chem. 264, 188284–18287 ( 1989).

    Google Scholar 

  12. Aglietta, M. et al. Kinetics of human hematopoietic cells after in vivo administration of granulocyte-macrophage colony-stimulating factor. J. Clin. Invest. 83, 551–557 (1989).

    Article  CAS  Google Scholar 

  13. Prokop, D.J. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276, 71–74 ( 1997).

    Article  Google Scholar 

  14. Perkins, S. & Fleischman, R.A. Stromal cell progeny of murine bone marrow fibroblast colony-forming units are clonal endothelial-like cells that express collagen IV and laminin. Blood 75, 620–625 (1990).

    CAS  Google Scholar 

  15. Fleischman, R., Simpson, A.F., Gallardo, T., Jin, X.L. & Perkins, S. Isolation of endothelial-like stromal cells that express Kit ligand and support in vitro hematopoiesis. Exp. Hematol. 23, 1407–1416 (1995).

    CAS  PubMed  Google Scholar 

  16. Kenyon, B.M. et al. A model of angiogenesis in the mouse cornea. Invest. Ophthalmol. Vis. Sci. 37, 1652–1632 (1996).

    Google Scholar 

  17. Asahara, T. et al. Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization. Circ. Res. 83, 233–240 ( 1998).

    Article  CAS  Google Scholar 

  18. Schlaeger, T.M., Qin, Y., Fujiwara, Y., Magram, J. & Sato, T.N. Vascular endothelial lineage-specific promoter in transgenic mice. Development 121, 1089– 1098 (1995).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Acknowledgments We would like to thank M. Neely for secretarial assisstance. The human reconbinant GM-CSF molecule was gift from T.L. Nagabhusham in Schering-Plough Research Institute. This work was supported by grants (HL 40518, HL02824, and HL57516) from the National Institutes of Health, Bethesda, Maryland. C.K. is supported in part by Cologne Fortune in Germany.

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Takahashi, T., Kalka, C., Masuda, H. et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5, 434–438 (1999). https://doi.org/10.1038/7434

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