Randomised comparison of G-CSF-mobilized peripheral blood mononuclear cells versus bone marrow-mononuclear cells for the treatment of patients with lower limb arteriosclerosis obliterans

Summary

Previous studies have suggested that the lower limb arteriosclerosis obliterans (LASO) could be improved by autologous transplantation of either bone marrow mononuclear cells (BMMNC) or G-CSF-mobilized peripheral blood mononuclear cells (M-PBMNC). However, the number of patients observed was very limited, and little information is available regarding comparison. The present randomised trial was designed to assess which is the better option. One hundred fifty patients with LASO were randomised to either group A (76 cases implanted with M-PBMNC) or group B (74 cases implanted with BMMNC), and followed up for 12 weeks. Primary outcomes were safety and efficacy of treatment, based on ankle-brachial index (ABI) and rest pain, and analysis was per protocol. Significant improvement of the main clinical index was observed in both groups after transplantation. No transplantation-related complication was observed in either group. Comparative analysis revealed that at 12 weeks after cell implantation, improvement of ABI (difference 0.06 ± 0.01; p<0.0001), skin temperature (difference 0.55 ± 0.25; p=0.028), and rest pain (difference –0.57 ± –0.15;p<0.0001) was significantly better in groupA patients than group B patients. However, there was no significant difference between two groups for pain-free walking distance, transcutaneous oxygen pressure, ulcers, and rate of lower limb amputation. Autologous transplantation of either M-PBMNC or BMMNC significantly promotes improvement of limb ischaemia in patients with LASO. Comparative analysis indicated that M-PBMNC should be more practical in comparison with BMMNC in the treatment of LASO.

Keywords

Peripheral vascular disease - angiogenesis - cells - therapy

• References

• 1 Boccalon H, Lehert P, Mosnier M. Assessment of the prevalence of atherosclerotic lower limb arteriopathy in France as a systolic index in a vascular risk population. J Mal Vasc 2000; 25: 38-46.
• 2 Goon PKY, Lip GYH. Arterial disease and venous thromboembolism: A modern paradigm?. Thrombosis and Haemostasis 2006; 96: 111-112.
• 3 Rao AK, Vaidyula VR, Bagga S. et al. Effect of antiplatelet agents clopidogrel, aspirin, and cilostazol on circulating tissue factor procoagulant activity in patients with peripheral arterial disease. Thromb Haemost 2006; 96: 738-743.
• 4 Miyajima S, Shirai A, Yamamoto S. et al. Risk factors for major limb amputations in diabetic foot gangrene patients. Diabetes Res Clin Pract 2006; 71: 272-279.
• 5 Asahara T, Murohara T, Sullivan A. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964-967.
• 6 Silvestre JS, Levy BI. Angiogenesis therapy in ischemic disease. Arch Mal Coeur Vaiss 2002; 95: 189-196.
• 7 Shintani S, Murohara T, Ikeda H. et al. Augmentation of postnatal neovascularization with autologous bone marrow transplantation. Circulation 2001; 103: 897-895.
• 8 Al-Khaldi A, Al-Sabti H, Galipeau J. et al. Therapeutic angiogenesis using autologous bone marrow stromal cells: improved blood flow in a chronic limb ischemia model. Ann Thorac Surg 2003; 75: 204-209.
• 9 Yoshida M, Horimoto H, Mieno S. et al. Intra-arterial bone marrow cell transplantation induces angiogenesis in rat hindlimb ischemia. Eur Surg Res 2003; 35: 86-91.
• 10 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: 427-435.
• 11 Koshikawa M, Shimodaira S, Yoshioka T. 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.
• 12 Saigawa T, Kato K, Ozawa T. et al. Clinical application of bone marrow implantation in patients with arteriosclerosis obliterans, and the association between efficacy and the number of implanted bone marrow cells. Circ J 2004; 68: 1189-1193.
• 13 Higashi Y, Kimura M, Hara K. et al. Autologous bone-marrow mononuclear cell implantation improves endothelium-dependent vasodilation in patients with limb ischemia. Circulation 2004; 109: 1215-1218.
• 14 Rehman J, Li J, Orschell CM. et al. Peripheral blood "endothelial progenitor cells" are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 2003; 107: 1164-1169.
• 15 Fan CL, Gao PJ, Che ZQ. et al. Therapeutic neovascularization by autologous transplantation with expanded endothelial progenitor cells from peripheral blood into ischemic hind limbs. Acta Pharmacol Sin 2005; 26: 1069-1075.
• 16 Hill JM, Zalos G, Halcox JPG. et al. Circulating endothelial progenitor cells, vascular function and cardiovascular risk. N Engl J Med 2003; 348: 593-600.
• 17 Dzau VJ, Gnecchi M, Pachori AS. et al. Therapeutic potential of endothelial progenitor cells in cardiovascular diseases. Hypertension 2005; 46: 7-18.
• 18 Iba O, Matsubara H, Nozawa Y. et al. Angiogenesis by implantation of peripheral blood mononuclear cells and platelets into ischemic limbs. Circulation 2002; 106: 2019-2025.
• 19 Schatteman GC, Hanlon HD, Jiao C. et al. Bloodderived angioblasts accelerate blood-flow restoration in diabetic mice. J Clin Invest 2000; 106: 571-578.
• 20 Takahashi T, Kalka C, Masuda H. et al. Ischaemia and cytokine-induced mobilization of bone marrowderived endothelial cells for neovascularization. Nat Med 1999; 5: 434-438.
• 21 Huang PP, Li SZ, Han MZ. et al. Autologous transplantation of peripheral blood stem cells as an effective therapeutic approach for severe arteriosclerosis obliterans of lower extremities. Thromb Haemost 2004; 91: 606-609.
• 22 Huang PP, Li SZ, Han MZ. et al. Autologous transplantation of granulocyte colony-stimulating factormobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care 2005; 28: 2155-2160.
• 23 Ishida A, Ohya Y, Sakuda H. et al. Autologous peripheral blood mononuclear cell implantation for patients with peripheral arterial disease improves limb ischemia. Circ J 2005; 69: 1260-1265.
• 24 Falanga V. Wound healing and its impairment in the diabetic foot. Lancet 2005; 366: 1736-1743.
• 25 Cavanagh PR, Lipsky BA, Bradbury AW. et al. Treatment for diabetic foot ulcers. Lancet 2005; 366: 1725-1735.
• 26 Treiman GS, Oderich GS, Ashrafi A. et al. Management of ischemic heel ulceration and gangrene: An evaluation of factors associated with successful healing. J Vasc Surg 2000; 31: 1110-1118.
• 27 Kawachi Y, Watanabe A, Uchida T. et al. Acute arterial thrombosis due to platelet aggregation in a patient receiving granulocyte colony-stimulating factor. Br J Haematol 1996; 94: 413-416.
• 28 Fukumoto Y, Miyamoto T, Okamura T. et al. Angina pectoris occurring during granulocyte colonystimulating factor-combined preparatory regimen for autologous peripheral blood stem cell transplantation in a patient with acute myelogenous leukaemia. Br J Haematol 1997; 97: 666-668.
• 29 Oyibo SO, Jude EB, Tarawneh I. et al. A comparison of two diabetic foot ulcer classification systems. Diabetes Care 2001; 24: 84-88.
• 30 Cavallaro AM, Lilleby K, Majolino I. et al. Three to six year follow-up of normal donors who received recombinant human granulocyte colony-stimulating factor. Bone Marrow Transplant 2000; 25: 85-89.
• 31 Powell TM, Paul JD, Hill JM. et al. Granulocyte colony- stimulating factor mobilizes functional endothelial progenitor cells in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2005; 25: 296-301.
• 32 Bussolino F, Ziche M, Wang JM. et al. In vitro and in vivo activation of endothelial cells by colony-stimulating factors. J Clin Invest 1991; 87: 986-995.
• 33 Seiler C, Pohl T, Wustmann K. et al. Promotion of collateral growth by granulocyte-macrophage colonystimulating factor in patients with coronary artery disease: a randomized, double-blind, placebo-controlled study. Circulation 2001; 104: 2012-2017.
• 34 Hristov M, Erl W, Weber PC. Endothelial progenitor cells: Mobilization, differentiation, and homing. Arterioscler Thromb Vasc Biol 2003; 23: 1185-1189.
• 35 Kalka C, Masuda H, Takahashi T. et al. Vascular endothelial growth factor (165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res 2000; 86: 1198-1202.
• 36 Li S, Zhou B, Han ZC. Therapeutic neovascularization by transplantation of mobilized peripheral blood mononuclear cells for limb ischemia. A comparison between CD34+ and CD34- mononuclear cells. Thromb Haemost 2006; 95: 301-311.
• 37 Yang C, Zhang ZH, Li ZJ. et al. Enhancement of neovascularization with cord blood CD133+ cell-derived endothelial progenitor cell transplantation. Thromb Haemost 2004; 91: 1202-1212.
• 38 Zhou B, Bi YY, Han ZB. et al. G-CSF-mobilized peripheral blood mononuclear cells from diabetic patients augment neovascularization in ischemic limbs but with impaired capability. J Thromb Haemost 2006; 4: 993-1002.
• 39 Frangogiannis NG. Chemokines in ischemia and reperfusion. Thromb Haemost 2007; 97: 738-747.
• 40 De Paula EV, Nascimento MCF, Ramos CD. et al. Early in vivo anticoagulation inhibits the angiogenic response following hindlimb ischemia in a rodent model. Thromb Haemost 2006; 96: 68-72.
• 41 Braunersreuther V, Mach F, Steffens S. The specific role of chemokines in atherosclerosis. Thromb Haemost 2007; 97: 714-721.
• 42 Kuethe F, Krack A, Fritzenwanger M. et al. Treatment with granulocyte-colony stimulating factor in patients with acute myocardial infarction. Evidence for a stimulation of neovascularization and improvement of myocardial perfusion. Pharmazie 2006; 61: 957-961.