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Autografting

Autologous peripheral blood CD133+ cell implantation for limb salvage in patients with critical limb ischemia

Bone Marrow Transplantation volume 45, pages 111–116 (2010)Cite this article

Abstract

We report the safety and feasibility of autologous CD133+ cell implantation into the lower extremity muscles of patients with critical limb ischemia, whose only other option was limb amputation. Nine patients participated in the study: seven patients suffering from arteriosclerosis obliterans, one with thromboangiitis obliterans (Buerger's disease) and one with thromboembolic disorder. Autologous PBSC were collected after the administration of G-CSF (10 mcg/kg/day). CD133+ cells were selected using the CLINIMACS cell separation device and were injected i.m. without earlier cryopreservation using a 22-gauge needle into multiple sites 3 cm apart in the gastrocnemius/soleus muscle, or depending on clinical circumstances, in the foot or quadriceps muscle, or both, of the involved leg. There were no complications from either leukapheresis or injection. Stem cell injection prevented leg amputation in seven of the nine patients. In this small cohort of patients with end-stage critical limb ischemia, quality of life (Short Form-36) physical component score improved significantly at 3 (P=0.02) and 6 (P=0.01) months, but not at 1 year (P=0.08). There was a trend towards the improvement in pain-free treadmill walking time (P=0.13) and exercise capacity (P=0.16) at 1 year. Lower extremity limb salvage was achieved for seven of the nine treated patients.

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References

  1. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA . Fowkes FGR on behalf of the TASC II Working Group Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007; 45: S5A–S65A.

    Article  Google Scholar 

  2. Baumgartner I, Schainfeld r, Graziani L . Management of peripheral vascular disease. Annu Rev Med 2005; 56: 249–272.

    Article  CAS  PubMed  Google Scholar 

  3. Cox GS, Hertzer NR, Young JR, O’Hara PJ, Krajewski LP, Piedmonte MR et al. Nonoperative treatment of superficial femoral artery disease: long-term follow up. J Vasc Surg 1993; 17: 172–182.

    Article  CAS  PubMed  Google Scholar 

  4. Leng GC, Lee AJ, Fowkes FG, Whiteman M, Dunbar J, Housley E et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol 1996; 25: 1172–1181.

    Article  CAS  PubMed  Google Scholar 

  5. Burt RK, Loh Y, Pearce W, Behoar N, Barr WG, Craig R et al. Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases. JAMA 2008; 299: 925–936.

    Article  CAS  PubMed  Google Scholar 

  6. Schatteman G . Are circulating CD 133+ cells biomarkers for vascular disease? Arterioscler Thromb Vasc Biol 2005; 25: 270–271.

    Article  PubMed  Google Scholar 

  7. Hristov M, Erl W, Weber PC . Endothelial progenitor cells. Isolation and characterization. Trends Cardiovasc Med 2003; 13: 201–206.

    Article  CAS  PubMed  Google Scholar 

  8. Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M et al. Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors. Blood 2000; 95: 952–958.

    CAS  PubMed  Google Scholar 

  9. Montgomery PS, Gardner AW . The clinical utility of a six-minute walk test in peripheral arterial occlusive disease patients. J Am Geriatr Soc 1998; 46: 706–711.

    Article  CAS  PubMed  Google Scholar 

  10. Hiatt WR, Wolfel EE, Meier RH, Regensteiner JG . Superiority of treadmill walking exercise versus strength training for patients with peripheral arterial disease. Implications for the mechanism of the training response. Circulation 1994; 90: 1866–1874.

    Article  CAS  PubMed  Google Scholar 

  11. Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF, Blazer DG et al. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol 1994; 49: M85–M94.

    Article  CAS  PubMed  Google Scholar 

  12. McDermott MM, Greenland P, Ferrucci L, Criqui MH, Liu K, Sharma L et al. Lower extremity performance is associated with daily life physical activity in individuals with and without peripheral arterial disease. J Am Geriatr Soc 2002; 50: 247–255.

    Article  PubMed  Google Scholar 

  13. Ware JE, Snow KK, Kosinski M, Gandek B . SF-36 Health Survey—Manual and Interpretation Guide. The Health Institute, New England Medical Center: Boston, MA, (1993).

  14. Ware JE, Sherbourne CD . The MOS 36-Item Short Form Health Survey (SF-36): I. Conceptual framework and item selection. Med Care 30 (1992), 473–483.

    Article  PubMed  Google Scholar 

  15. Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H et al Therapeutic Angiogenesis using Cell Transplantation (TACT) Study Investigators. 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: 427–435.

    Article  PubMed  Google Scholar 

  16. Ishida A, Ohya Y, Sakuda H, Ohshiro K, Higashiuesato Y, Nakaema M et al. Autologous peripheral blood mononuclear cell implantation for patients with Peripheral Arterial Disease improves limb ischemia. Circ J 2005; 69: 1260–1265.

    Article  PubMed  Google Scholar 

  17. Feinglass J, McCarthy WJ, Slavensky R, Manheim LM, Martin GJ . Functional status and walking ability after lower extremity bypass grafting or angioplasty for intermittent claudication: results from a prospective outcomes study. J Vasc Surg 2000; 31: 93–103.

    Article  CAS  PubMed  Google Scholar 

  18. Regensteiner JG, Gardner A, Hiatt WR . Exercise testing and exercise rehabilitation for patients with peripheral arterial disease: Status in 1997. Vasc Med 1997; 2: 147–155.

    Article  CAS  PubMed  Google Scholar 

  19. Iba O, Matsubara H, Nozawa Y, Fujiyama S, Amano K, Mori Y et al. Angiogenesis by implantation of peripheral blood mononuclear cells and platelets into ischemic limbs. Circulation 2002; 106: 2019–2025.

    Article  CAS  PubMed  Google Scholar 

  20. Ziegelhoeffer T, Fernandez B, Kostin S, Heil M, Voswinckel R, Helisch A et al. Bone marrow-derived cells do not incorporate into the adult growing vasculature. Circ Res 2004; 94: 230–238.

    Article  CAS  PubMed  Google Scholar 

  21. Kamihata H, Matsubara H, Nishiue T, Fujiyama S, Tsutsumi Y, Ozono R et al Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokine. Circulation 2001; 104: 1046–1052.

    Article  CAS  PubMed  Google Scholar 

  22. Nizankowski R, Petriczek T, Skotnicki A, Szczeklik A . The treatment of advanced chronic lower limb ischaemia with marrow stem cell autotransplantation. Kardiol Pol (2005); 63: 351–360.

    PubMed  Google Scholar 

  23. Kawamura A, Takashi H, Ichiro T, Yoshihiro A, Yamada M, Egawa H et al Clinical study of therapeutic angiogenesis by autologous peripheral blood stem cell (PBSC) transplantation in 92 patients with critically ischemic limbs. J Artif Organs 2006; 9: 226–233.

    Article  PubMed  Google Scholar 

  24. Durdu S, Akar AR, Arat M, Sancak T, Eren NT, Ozyurda U . Autologous bone-marrow mononuclear cell implantation for patients with Rutherford grade II-III thromboangiitis obliterans. J Vasc Surg 2006; 44: 732–739.

    Article  PubMed  Google Scholar 

  25. Kim DI, Kim MJ, Joh JH, Shin SW, Do YS, Moon JY et al. Angiogenesis facilitated by autologous whole bone marrow stem cell transplantation for Buerger's Disease. Stem Cells 2006; 24: 1194–1200.

    Article  PubMed  Google Scholar 

  26. Hernandez P, Cortina L, Artaza H, Pol N, Lam RM, Dorticos E et al. Autologous bone-marrow mononuclear cell implantation in patients with severe lower limb ischaemia: a comparison of using blood cell separator and ficoll density gradient centrifugation. Atherosclerosis 2007; 194: e52–e56.

    Article  CAS  PubMed  Google Scholar 

  27. Inaba S, Egashira K, Komori K . Peripheral Blood or bone-marrow mononuclear cells for therapeutic angiogenesis? The Lancet 2002; 360: 2083.

    Article  Google Scholar 

  28. Bartsch T, Brehm, M, Zeus T, Kogler G, Wernet P, Strauer B.E . Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (the TAM-PAD study). Clin Res Cardiol 2007; 96: 891–899.

    Article  CAS  PubMed  Google Scholar 

  29. Kolvenbach R, Kreissig R, Ludwig E, Cagiannos C . Stem cell use in critical limb ischemia. J Caridovasc Surg 2007; 48: 39–44.

    CAS  Google Scholar 

  30. Koshikawa M, Shimodaira S, Yoshioka T, Kasai H, Watanabe N, Wada Y et al. Therapeutic angiogenesis by bone marrow implantation for critical hand ischemia in patients with peripheral arterial disease: a pilot study. Curr Med Res Opin 2006; 22: 793–798.

    Article  PubMed  Google Scholar 

  31. Lenk K, Adams V, Lurz P, Erbs S, Linke A, Gielen S et al. Therapeutical potential of blood-derived progenitor cells in patients with peripheral arterial occlusive disease and critical limb ischaemia. Eur Heart J (2005); 26: 1903–1909.

    Article  PubMed  Google Scholar 

  32. Kajiguchi M, Kondo T, Izawa H, Kobayashi M, Yamamoto K, Shintani S et al Safety and efficacy of autologous progenitor cell transplantation for therapeutic angiogenesis in patients with critical limb ischemia. Circ J 2007; 71: 196–201.

    Article  PubMed  Google Scholar 

  33. Ishida A, Ohya Y, Sakuda H, Ohshiro K, Higashiuesato Y, Nakaema M et al. Autologous peripheral blood mononuclear cell implantation for patients with peripheral arterial disease improves limb ischemia. Circ J 2005; 69: 1260–1265.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Immunotherapy, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    R K Burt, A Testori, Y Oyama, K Yaung, M Villa, J M Bucha & F Milanetti

  2. Department of Vascular Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    H E Rodriguez & W H Pearce

  3. Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    J Sheehan

  4. Department of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    N Rajamannan

  5. Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    N Rajamannan

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  1. R K Burt
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  2. A Testori
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  4. H E Rodriguez
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Correspondence to R K Burt.

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Burt, R., Testori, A., Oyama, Y. et al. Autologous peripheral blood CD133+ cell implantation for limb salvage in patients with critical limb ischemia. Bone Marrow Transplant 45, 111–116 (2010). https://doi.org/10.1038/bmt.2009.102

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  • DOI: https://doi.org/10.1038/bmt.2009.102

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