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Thromb Haemost 2006; 95(02): 301-311
DOI: 10.1160/TH05-06-0442
Endothelium and Vascular Development
Schattauer GmbH

Therapeutic neovascularization by transplantation of mobilized peripheral blood mononuclear cells for limb ischemia

A comparison between CD34+ and CD34− mononuclear cells
Shu Li   *
1   State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College; National Research Center for Cell Products Engineering, AmCellgene Co. Ltd, Tianjin, People’s Republic of China
,
Bin Zhou   *
1   State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College; National Research Center for Cell Products Engineering, AmCellgene Co. Ltd, Tianjin, People’s Republic of China
,
Zhong Chao Han
1   State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College; National Research Center for Cell Products Engineering, AmCellgene Co. Ltd, Tianjin, People’s Republic of China
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Publikationsverlauf

Received 25. Juni 2005

Accepted after resubmission 21. Januar 2005

Publikationsdatum:
28. November 2017 (online)

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Summary

Autolougous transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized human peripheral blood mononuclear cells (PBMNCs) improves limb ischemia in patients with arteriosclerosis obliterans of lower extremities and with diabetic foot. However, the mechanism of action of PBMNCs remains elusive. Here, we studied comparatively the effects of the G-CSF-mobilized PBMNCs and CD34-depleted G-CSF-mobilized PBMNCs in an ischemia model of athymic nude mice. Fluorescence-labeled human PBMNCs [1×106] were intramuscularly injected into the unilateral ischemic hindlimbs of mice. Laser Doppler imaging analysis revealed a significantly augmented blood perfusion at day 7, 14 and 28 after operation. The capillary density was also markedly increased and the rate of limb loss was significantly reduced in cell-transplanted groups when compared with those in PBS group. In comparison with G-CSF-mobilized PBMNCs, the therapeutic efficiency of G-CSF-mobilized PBMNCs deprived of CD34+ cells was impaired. Transplanted cells were found to accumulate around arterioles and scatter in capillary networks. Incorporation of transplanted cells into new capillaries was observed in the G-CSF-mobilized PBMNCs group, but was not detected in the group deprived of CD34+ cells. There was an elevated expression of VEGF in ischemic tissue. Colocalization of VEGF and transplanted mononuclear cells within adductor tissue was demonstrated. These findings indicate that G-CSF-mobilized PBMNCs promote vascular growth not only by incorporating into vessel walls but also by supplying angiogenic factors. The depletion of CD34+ cells attenuated the therapeutic efficiency of G-CSF-mobilized PBMNCs in response to ischemia-induced neovascularization.

Keywords

G-CSF-mobilized PBMNCs - ischemia - neovascularization - CD34 - VEGF

* Authors contributed equally to this work.


 

  • References

  • 1 Schaper W, Ito WD. Molecular mechanisms of coronary collateral vessel growth. Circ Res 1996; 79: 911-9.
    CrossrefPubMedGoogle Scholar
  • 2 Arras M, Ito WD. Monocyte activation in angiogenesis and collateral growth in the measured rabbit hindlimb. J Clin Invest 1998; 101: 40-50.
    CrossrefPubMedGoogle Scholar
  • 3 Ito WD, Arras M, Winkler B. et al. Angiogenesis but not collateral growth is associated with ischemia femoral artery occlusion. Am J Physiol 1997; 273: H1255-H1265.
    PubMedGoogle Scholar
  • 4 Kern MJ. Angiogenesis, arteriogenesis, and physiological perfusion: Review of natural history and concepts. J Interv Cardiol 1999; 12: 313-8.
    CrossrefPubMedGoogle Scholar
  • 5 Asahara T, Murohara T, Sullivan A. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964-7.
    CrossrefPubMedGoogle Scholar
  • 6 Murohara T, Ikeda H, Duan J. et al. Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest 2000; 105: 1527-36.
    CrossrefPubMedGoogle Scholar
  • 7 Kalka C, Masuda H, Taakahashi T. et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci US A 2000; 97: 3422-7.
    CrossrefPubMedGoogle Scholar
  • 8 Kawamoto A, Gwon HC, Iwaguro H. et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation 2001; 103: 634-7.
    CrossrefPubMedGoogle Scholar
  • 9 Schatteman GC, Hanlon HD, Jiao C. et al. Bloodderived angioblasts accelerate blood flow restoration in diabetic mice. J Clin Invest 2000; 106: 571-8.
    CrossrefPubMedGoogle Scholar
  • 10 Kocher AA, Schuster MD, Szabolcs MJ. et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001; 07: 430-6.
    CrossrefPubMedGoogle Scholar
  • 11 Shintani S, Murohara T, Ikeda H. et al. Augmentation of postnatal neovascularization with autologous bone marrow transplantation. Circulation 2001; 103: 897-903.
    CrossrefPubMedGoogle Scholar
  • 12 Minamino T, Toko H, Tateno K. et al. Peripheralblood or bone-marrow mononuclear cells for therapeutic angiogenesis?. Lancet 2002; 360: 2083-4.
    CrossrefPubMedGoogle Scholar
  • 13 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.
    CrossrefPubMedGoogle Scholar
  • 14 Huang PP, Li SZ, Han MZ. et al. Autologous transplantation of peripheral blood stem cells as treatment for arteriosclerosis obliterans of lower extremities. Thromb Haemost 2004; 91: 606-9.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 15 Wagers AJ, Sherwood RI, Christensen JL. et al. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002; 297: 2256-9.
    CrossrefPubMedGoogle Scholar
  • 16 Iba O, Matsubara H, Nozawa Y. et al. Angiogenesis by implantation of peripheral blood mononuclear cells and platelets into ischemic limb. Circulation 2002; 106: 2019-25.
    CrossrefPubMedGoogle Scholar
  • 17 Tibor Z, Borja F, Sawa K. et al. Bone marrow- derived cells do not Incorporate into the adult growing vasculature. Circ Res 2004; 94: 230-8.
    CrossrefPubMedGoogle Scholar
  • 18 Arras M, Ito WD, Scholz D. et al. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest 1998; 101: 40-50.
    CrossrefPubMedGoogle Scholar
  • 19 Takeshita S, Isshiki T, Mori H. et al. Microangiographic assessment of collateral vessel formation following direct gene transfer of vascular endothelial growth factor in rats. Cardiovasc Res 1997; 35: 547-52.
    CrossrefPubMedGoogle Scholar
  • 20 Asahara T, Masuda H, Takahashi T. et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999; 85: 221-8.
    CrossrefPubMedGoogle Scholar
  • 21 Noishiki Y, Tomizawa Y, Yamane Y. et al. Autocrine angiogenic vascular prosthesis with bone marrow transplantation. Nature Med 1996; 02: 90-3.
    CrossrefPubMedGoogle Scholar
  • 22 Asahara T, Takahashi T, Masuda H. et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 1999; 18: 3964-72.
    CrossrefPubMedGoogle Scholar
  • 23 Huang P, Li S, Han M. et al. Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care 2005; 28: 2155-60.
    CrossrefPubMedGoogle Scholar
  • 24 Heil M, Ziegelhoeffer T, Pipp F. et al. Blood monocyte concentration is critical for enhancement of collateral artery growth. Am J Physiol Heart Circ Physiol 2002; 283: H2411-H2419.
    CrossrefPubMedGoogle Scholar
  • 25 Arras M, Ito WD, Scholz D. et al. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest 1997; 101: 40-50.
    PubMedGoogle Scholar
  • 26 Rehman J, Li J, Orschell C. et al. Peripheral blood endothelial progenitor cells are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 2003; 107: 1164-9.
    CrossrefPubMedGoogle Scholar
  • 27 Fernandez BPujol, Lucibello FC, Gehling UM. et al. Endothelial-like cells derived from human CD14 positive monocytes. Differentiation 2000; 65: 287-300.
    CrossrefPubMedGoogle Scholar
  • 28 Schmeisser A, Garlichs CD, Zhang H. et al. Monocytes coexpress endothelial and macrophagocytic lineage markers and form cord-like structures in Matrigel under angiogenic conditions. Cardiovasc Res 2001; 49: 671-80.
    CrossrefPubMedGoogle Scholar
  • 29 Hershey JC, Baskin EP, Glass JD. et al. Revascularization in the rabbit hindlimb: dissociation between capillary sprouting and arteriogenesis. Cardiovasc Res 200 49: 618-25.
    PubMedGoogle Scholar
  • 30 Bergers G, Brekken R, McMahon G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000; 02: 737-44.
    CrossrefPubMedGoogle Scholar
  • 31 Clauss M, Gerlach M, Gerlach H. et al. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med 1990; 172: 1535-45.
    CrossrefPubMedGoogle Scholar
  • 32 Barleon B, Sozzani S, Zhou D. et al. Migration of human monocytes in response to vascular endothelial growth factor is mediated via the VEGF receptor flt-1 receptor. Blood 1996; 97: 3336-43.
    PubMedGoogle Scholar