Stem cell and progenitor cell therapy in peripheral artery disease

 

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Summary

Atherosclerotic peripheral artery disease (PAD) is a common manifestation of atherosclerosis. The occlusion of large limb arteries leads to ischaemia with claudication which can progress to critical limb ischaemia (CLI) with pain at rest, and to tissue loss. At present, common therapy for CLI is either surgical or endovascular revascularisation aimed at improving blood flow to the affected extremity. However, major amputation and death are still frequent complications. Exploring new strategies for revascularisation of ischaemic limbs is thus of major importance. Bone marrow (BM)-derived stem and progenitor cells have been identified as a potential new therapeutic option to induce therapeutic angiogenesis. Encouraging results of preclinical studies have rapidly led to several small clinical trials, in which BM-derived mononuclear cells were administered to patients with limb ischaemia. Clinical benefits were reported from these trials including improvement of ankle-brachial index (ABI), transcutaneous partial pressure of oxygen (TcPO₂), re-duction of pain, and decreased need for amputation. Nonetheless, large randomised, placebo-controlled, double-blind studies are necessary and currently ongoing (BONMOT-CLI, JUVENTUS and NCT00498069). Further research relates to the optimal cell type and dosage, the isolation method, the role of colony-stimulating factors, administration route, and the supportive stimulation of cells with reduced functioning due to advanced PAD. Autologous stem cell therapy for ischaemic peripheral disease seems to be a promising new tool for the treatment of severe limb ischaemia. Preliminary evidence has established its safety, feasibility and effectiveness on several important endpoints. Several large endpoints studies are underway to further consolidate this evidence.

• References

• 1 Olin JW. Thromboangiitis obliterans (Buerger’s disease). N Engl J Med 2000; 343: 864-869.
  CrossrefPubMedGoogle Scholar
• 2 Ness J, Aronow WS. Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital-based geriatrics practice. J Am Geriatr Soc 1999; 47: 1255-1256.
  CrossrefPubMedGoogle Scholar
• 3 Adam DJ, Beard JD, Cleveland T. et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet 2005; 366: 1925-1934.
  CrossrefPubMedGoogle Scholar
• 4 Hirsch AT, Haskal ZJ, Hertzer NR. et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006; 113: e463-e654.
  CrossrefPubMedGoogle Scholar
• 5 Hershey JC, Baskin EP, Glass JD. et al. Revascularization in the rabbit hindlimb: dissociation between capillary sprouting and arteriogenesis. Cardiovasc Res 2001; 49: 618-625.
  CrossrefPubMedGoogle Scholar
• 6 Ito WD, Arras M, Scholz D. et al. Angiogenesis but not collateral growth is associated with ischemia after femoral artery occlusion. Am J Physiol 1997; 273: H1255-H1265.
  PubMedGoogle Scholar
• 7 Hirota K, Semenza GL. Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol 2006; 59: 15-26.
  CrossrefPubMedGoogle Scholar
• 8 Buschmann I, Schaper W. The pathophysiology of the collateral circulation (arteriogenesis). J Pathol 2000; 190: 338-342.
  CrossrefPubMedGoogle Scholar
• 9 Heilmann C, Beyersdorf F, Lutter G. Collateral growth: cells arrive at the construction site. Cardiovasc Surg 2002; 10: 570-578.
  CrossrefPubMedGoogle Scholar
• 10 Diehm C, Trampisch H, Haberl R. et al. Prognosis of patients with asymptomatic versus symptomatic peripheral arterial disease (PAD): 3-year results of the getABI study. Vasc Med 2007; 12: 141-148.
  PubMedGoogle Scholar
• 11 Schirmer SH, van Nooijen FC, Piek JJ. et al. Stimulation of collateral artery growth: travelling further down the road to clinical application. Heart 2009; 95: 191-197.
  PubMedGoogle Scholar
• 12 Schaper W. Collateral circulation: past and present. Basic Res Cardiol 2009; 104: 5-21.
  CrossrefPubMedGoogle Scholar
• 13 Unthank JL, Sheridan KM, Dalsing MC. Collateral growth in the peripheral circulation: a review. Vasc Endovascular Surg 2004; 38: 291-313.
  CrossrefPubMedGoogle Scholar
• 14 Pipp F, Boehm S, Cai WJ. et al. Elevated fluid shear stress enhances postocclusive collateral artery growth and gene expression in the pig hind limb. Arterioscler Thromb Vasc Biol 2004; 24: 1664-1668.
  CrossrefPubMedGoogle Scholar
• 15 Schierling W, Troidl K, Troidl C, Schmitz-Rixen T, Schaper W, Eitenmuller IK. The role of angiogenic growth factors in arteriogenesis. J Vasc Res 2009; 46: 365-374.
  CrossrefPubMedGoogle Scholar
• 16 Heil M, Eitenmuller I, Schmitz-Rixen T. et al. Arteriogenesis versus angiogenesis: similarities and differences. J Cell Mol Med 2006; 10: 45-55.
  CrossrefPubMedGoogle Scholar
• 17 Chappell DC, Varner SE, Nerem RM. et al. Oscillatory shear stress stimulates adhesion molecule expression in cultured human endothelium. Circ Res 1998; 82: 532-539.
  CrossrefPubMedGoogle Scholar
• 18 Ziegelhoeffer T, Fernandez B, Kostin S. et al. Bone marrow-derived cells do not incorporate into the adult growing vasculature. Circ Res 2004; 94: 230-238.
  CrossrefPubMedGoogle Scholar
• 19 Kinnaird T, Stabile E, Burnett MS. et al. Bone-marrow-derived cells for enhancing collateral development: mechanisms, animal data, and initial clinical experiences. Circ Res 2004; 95: 354-363.
  CrossrefPubMedGoogle Scholar
• 20 Heil M, Ziegelhoeffer T, Mees B. et al. A different outlook on the role of bone marrow stem cells in vascular growth: bone marrow delivers software not hardware. Circ Res 2004; 94: 573-574.
  CrossrefPubMedGoogle Scholar
• 21 Asahara T, Murohara T, Sullivan A. et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964-967.
  CrossrefPubMedGoogle Scholar
• 22 Rohde E, Malischnik C, Thaler D. et al. Blood monocytes mimic endothelial progenitor cells. Stem Cells 2006; 24: 357-367.
  CrossrefPubMedGoogle Scholar
• 23 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.
  CrossrefPubMedGoogle Scholar
• 24 Egan CG, Caporali F, Huqi AF. et al. Reduced levels of putative endothelial progenitor and CXCR4+ cells in coronary artery disease: kinetics following percutaneous coronary intervention and association with clinical characteristics. Thromb Haemost 2009; 101: 1138-1146.
  Article in Thieme ConnectPubMedGoogle Scholar
• 25 Smadja DM, Godier A, Susen S. et al. Endothelial progenitor cells are selectively mobilised immediately after coronary artery bypass grafting or valve surgery. Thromb Haemost 2009; 101: 983-985.
  Article in Thieme ConnectPubMedGoogle Scholar
• 26 Dimmeler S, Leri A. Aging and disease as modifiers of efficacy of cell therapy. Circ Res 2008; 102: 1319-1330.
  CrossrefPubMedGoogle Scholar
• 27 Loomans CJ, de Koning EJ, Staal FJ. et al. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes 2004; 53: 195-199.
  CrossrefPubMedGoogle Scholar
• 28 Tepper OM, Galiano RD, Capla JM. et al. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 2002; 106: 2781-2786.
  CrossrefPubMedGoogle Scholar
• 29 Vasa M, Fichtlscherer S, Aicher A. et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001; 89: E1-E7.
  CrossrefPubMedGoogle Scholar
• 30 Kondo T, Hayashi M, Takeshita K. et al. Smoking cessation rapidly increases circulating progenitor cells in peripheral blood in chronic smokers. Arterioscler Thromb Vasc Biol 2004; 24: 1442-1447.
  CrossrefPubMedGoogle Scholar
• 31 Imanishi T, Hano T, Sawamura T. et al. Oxidized low-density lipoprotein induces endothelial progenitor cell senescence, leading to cellular dysfunction. Clin Exp Pharmacol Physiol 2004; 31: 407-413.
  CrossrefPubMedGoogle Scholar
• 32 Zhu S, Liu X, Li Y. et al. Aging in the atherosclerosis milieu may accelerate the consumption of bone marrow endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2007; 27: 113-119.
  CrossrefPubMedGoogle Scholar
• 33 Shintani S, Murohara T, Ikeda H. et al. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 2001; 103: 2776-2779.
  CrossrefPubMedGoogle Scholar
• 34 Takahashi T, Kalka C, Masuda H. et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 1999; 05: 434-438.
  CrossrefPubMedGoogle Scholar
• 35 Asahara T, Masuda H, Takahashi T. et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circulation Res 1999; 85: 221-228.
  CrossrefPubMedGoogle Scholar
• 36 Kamihata H, Matsubara H, Nishiue T. et al. Implantation of bone marrow mono-nuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 2001; 104: 1046-1052.
  CrossrefPubMedGoogle Scholar
• 37 Kalka C, Masuda H, Takahashi T. et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci USA 2000; 97: 3422-3427.
  CrossrefPubMedGoogle Scholar
• 38 Gulati R, Simari RD. Defining the potential for cell therapy for vascular disease using animal models. Dis Model Mech 2009; 02: 130-137.
  CrossrefPubMedGoogle Scholar
• 39 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.
  CrossrefPubMedGoogle Scholar
• 40 Strauer BE, Brehm M, Zeus T. et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002; 106: 1913-1918.
  CrossrefPubMedGoogle Scholar
• 41 Rutherford RB, Baker JD, Ernst C. et al. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg 1997; 26: 517-538.
  CrossrefPubMedGoogle Scholar
• 42 Timmermans F, Plum J, Yoder MC. et al. Endothelial progenitor cells: identity defined?. J Cell Mol Med 2009; 13: 87-102.
  PubMedGoogle Scholar
• 43 Timmermans F, Van HF, De SM. et al. Endothelial outgrowth cells are not derived from CD133+ cells or CD45+ hematopoietic precursors. Arterioscler Thromb Vasc Biol 2007; 27: 1572-1579.
  CrossrefPubMedGoogle Scholar
• 44 Purhonen S, Palm J, Rossi D. et al. Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc Natl Acad Sci USA 2008; 105: 6620-6625.
  CrossrefPubMedGoogle Scholar
• 45 Canizo MC, Lozano F, Gonzalez-Porras JR. et al. Peripheral endothelial progenitor cells (CD133 +) for therapeutic vasculogenesis in a patient with critical limb ischemia. One year follow-up. Cytotherapy 2007; 09: 99-102.
  CrossrefPubMedGoogle Scholar
• 46 Kudo FA, Nishibe T, Nishibe M. et al. Autologous transplantation of peripheral blood endothelial progenitor cells (CD34+) for therapeutic angiogenesis in patients with critical limb ischemia. Int Angiol 2003; 22: 344-348.
  PubMedGoogle Scholar
• 47 Iohara K, Zheng L, Wake H. et al. A novel stem cell source for vasculogenesis in ischemia: subfraction of side population cells from dental pulp. Stem Cells 2008; 26: 2408-2418.
  CrossrefPubMedGoogle Scholar
• 48 Sanz-Ruiz R, Fernandez-Santos E, Dominguez-Munoa M. et al. Early translation of adipose-derived cell therapy for cardiovascular disease. Cell Transplant 2009; 18: 245-254.
  CrossrefPubMedGoogle Scholar
• 49 Murphy MP, Wang H, Patel AN. et al. Allogeneic endometrial regenerative cells: an “Off the shelf solution” for critical limb ischemia?. J Transl Med 2008; 06: 45.
  CrossrefPubMedGoogle Scholar
• 50 Huang YC, Yang ZM, Chen XH. et al. Isolation of Mesenchymal Stem Cells from Human Placental Decidua Basalis and Resistance to Hypoxia and Serum Deprivation. Stem Cell Rev Rep. 2009 prepub online doi:10.1007s12015-009-09069.
  PubMedGoogle Scholar
• 51 Finney MR, Greco NJ, Haynesworth SE. et al. Direct comparison of umbilical cord blood versus bone marrow-derived endothelial precursor cells in mediating neovascularization in response to vascular ischemia. Biol Blood Marrow Transplant 2006; 12: 585-593.
  CrossrefPubMedGoogle Scholar
• 52 Boyum A. Separation of lymphocytes, lymphocyte subgroups and monocytes: a review. Lymphology 1977; 10: 71-76.
  PubMedGoogle Scholar
• 53 Boyum A. Separation of lymphocytes, granulocytes, and monocytes from human blood using iodinated density gradient media. Methods Enzymol 1984; 108: 88-102.
  PubMedGoogle Scholar
• 54 Boyum A, Lovhaug D, Tresland L. et al. Separation of leucocytes: improved cell purity by fine adjustments of gradient medium density and osmolality. Scand J Immunol 1991; 34: 697-712.
  CrossrefPubMedGoogle Scholar
• 55 Boyum A, Brincker FH, Martinsen I. et al. Separation of human lymphocytes from citrated blood by density gradient (NycoPrep) centrifugation: monocyte depletion depending upon activation of membrane potassium channels. Scand J Immunol 2002; 56: 76-84.
  CrossrefPubMedGoogle Scholar
• 56 Prochazka V, Gumulec J, Chmelova J. et al. Autologous bone marrow stem cell transplantation in patients with end-stage chronical critical limb ischemia and diabetic foot. Vnitr Lek 2009; 55: 173-178.
  PubMedGoogle Scholar
• 57 Amann B, Luedemann C, Ratei R. et al. Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease. Cell Transplant 2009; 18: 371-380.
  CrossrefPubMedGoogle Scholar
• 58 Lenk K, Adams V, Lurz P. 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.
  CrossrefPubMedGoogle Scholar
• 59 Gastens MH, Goltry K, Prohaska W. et al. Good manufacturing practice-compliant expansion of marrow-derived stem and progenitor cells for cell therapy. Cell Transplant 2007; 16: 685-696.
  CrossrefPubMedGoogle Scholar
• 60 Hermann PC, Huber SL, Herrler T. et al. Concentration of bone marrow total nucleated cells by a point-of-care device provides a high yield and preserves their functional activity. Cell Transplant 2008; 16: 1059-1069.
  PubMedGoogle Scholar
• 61 Kawamura A, Horie T, Tsuda I. 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; 09: 226-233.
  CrossrefPubMedGoogle Scholar
• 62 Huang PP, Yang XF, Li SZ. et al. 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. Thromb Haemost 2007; 98: 1335-1342.
  Article in Thieme ConnectPubMedGoogle Scholar
• 63 Schachinger V, Assmus B, Britten MB. et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol 2004; 44: 1690-1699.
  CrossrefPubMedGoogle Scholar
• 64 Hernandez P, Cortina L, Artaza H. 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.
  CrossrefPubMedGoogle Scholar
• 65 Seeger FH, Tonn T, Krzossok N. et al. Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. Eur Heart J 2007; 28: 766-772.
  CrossrefPubMedGoogle Scholar
• 66 Janssens S, Dubois C, Bogaert J. et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 2006; 367: 113-121.
  CrossrefPubMedGoogle Scholar
• 67 Schachinger V, Erbs S, Elsasser A. et al. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J 2006; 27: 2775-2783.
  CrossrefPubMedGoogle Scholar
• 68 Sprengers RW, Lips DJ, Moll FL. et al. Progenitor cell therapy in patients with critical limb ischemia without surgical options. Ann Surg 2008; 247: 411-420.
  CrossrefPubMedGoogle Scholar
• 69 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.
  CrossrefPubMedGoogle Scholar
• 70 Durdu S, Akar AR, Arat M. et al. Autologous bone-marrow mononuclear cell implantation for patients with Rutherford grade II-III thromboangiitis obliterans. J Vasc Surg 2006; 44: 732-739.
  CrossrefPubMedGoogle Scholar
• 71 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.
  CrossrefPubMedGoogle Scholar
• 72 Gyongyosi M, Lang I, Dettke M. et al. Combined delivery approach of bone marrow mononuclear stem cells early and late after myocardial infarction: the MYSTAR prospective, randomized study. Nat Clin Pract Cardiovasc Med 2009; 06: 70-81.
  CrossrefPubMedGoogle Scholar
• 73 Honold J, Lehmann R, Heeschen C. et al. Effects of granulocyte colony simulating factor on functional activities of endothelial progenitor cells in patients with chronic ischemic heart disease. Arterioscler Thromb Vasc Biol 2006; 26: 2238-2243.
  CrossrefPubMedGoogle Scholar
• 74 Dreger P, Schmitz N. Stem Cell Mobilization in Healthy Donors: Current Status. Infusionstherapie und Transfusionsmedizin 1999; 26: 92-95.
  PubMedGoogle Scholar
• 75 Johnsen HE. Clinical practice and future needs in recombinant human granulocyte colony-stimulating factor treatment: a review of randomized trials in clinical haemato-oncology. J Int Med Res 2001; 29: 87-99.
  CrossrefPubMedGoogle Scholar
• 76 Buschmann IR, Hoefer IE, van Royen N. et al. GM-CSF: a strong arteriogenic factor acting by amplification of monocyte function. Atherosclerosis 2001; 159: 343-356.
  CrossrefPubMedGoogle Scholar
• 77 Terrovitis J, Charitos C, Dolou P. et al. No effect of stem cell mobilization with GM-CSF on infarct size and left ventricular function in experimental acute myocardial infarction. Basic Res Cardiol 2004; 99: 241-246.
  PubMedGoogle Scholar
• 78 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: 2155-2160.
  CrossrefPubMedGoogle Scholar
• 79 Shi Q, Hodara V, Butler SD. et al. Differential bone marrow stem cell mobilization by G-CSF injection or arterial ligation in baboons. J Cell Mol Med 2008; 13: 1896-1906.
  PubMedGoogle Scholar
• 80 Assmus B, Schachinger V, Teupe C. et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 2002; 106: 3009-3017.
  CrossrefPubMedGoogle Scholar
• 81 Thompson CA, Reddy VK, Srinivasan A. et al. Left ventricular functional recovery with percutaneous, transvascular direct myocardial delivery of bone marrow-derived cells. J Heart Lung Transplant 2005; 24: 1385-1392.
  CrossrefPubMedGoogle Scholar
• 82 Zhang M, Methot D, Poppa V. et al. Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. J Mol Cell Cardiol 2001; 33: 907-921.
  CrossrefPubMedGoogle Scholar
• 83 Tran N, Li Y, Maskali F. et al. Short-term heart retention and distribution of intramyocardial delivered mesenchymal cells within necrotic or intact myocardium. Cell Transplant 2006; 15: 351-358.
  CrossrefPubMedGoogle Scholar
• 84 Amann B, Ludemann C, Ruckert R. et al. Design and rationale of a randomized, double-blind, placebo-controlled phase III study for autologous bone marrow cell transplantation in critical limb ischemia: the BONe Marrow Outcomes Trial in Critical Limb Ischemia (BONMOT-CLI). VASA 2008; 37: 319-325.
  CrossrefPubMedGoogle Scholar
• 85 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.
  CrossrefPubMedGoogle Scholar
• 86 Bartsch T, Brehm M, Zeus T. et al. Autologous mononuclear stem cell transplantation in patients with peripheral occlusive arterial disease. J Cardiovasc Nurs 2006; 21: 430-432.
  CrossrefPubMedGoogle Scholar
• 87 Strauer BE, Brehm M, Zeus T. et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002; 106: 1913-1918.
  CrossrefPubMedGoogle Scholar
• 88 Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest 2005; 115: 572-583.
  CrossrefPubMedGoogle Scholar
• 89 Bartsch T, Brehm M, Zeus T. et al. Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (the TAMPAD study). Clin Res Cardiol 2007; 96: 891-899.
  CrossrefPubMedGoogle Scholar
• 90 Van Tongeren RB, Hamming JF, Fibbe WE. et al. Intramuscular or combined intramuscular/intra-arterial administration of bone marrow mononuclear cells: a clinical trial in patients with advanced limb ischemia. J Cardiovasc Surg 2008; 49: 51-58.
  PubMedGoogle Scholar
• 91 Vasa M, Fichtlscherer S, Aicher A. et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circulation Res 2001; 89: E1-E7.
  CrossrefPubMedGoogle Scholar
• 92 Fadini GP, Sartore S, Albiero M. et al. Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol 2006; 26: 2140-2146.
  CrossrefPubMedGoogle Scholar
• 93 Heeschen C, Lehmann R, Honold J. et al. Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation 2004; 109: 1615-1622.
  CrossrefPubMedGoogle Scholar
• 94 Dimmeler S, Aicher A, Vasa M. et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 2001; 108: 391-397.
  CrossrefPubMedGoogle Scholar
• 95 Llevadot J, Murasawa S, Kureishi Y. et al. HMG-CoA reductase inhibitor mobilizes bone marrow--derived endothelial progenitor cells. J Clin Invest 2001; 108: 399-405.
  CrossrefPubMedGoogle Scholar
• 96 Vasa M, Fichtlscherer S, Adler K. et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001; 103: 2885-2890.
  CrossrefPubMedGoogle Scholar
• 97 Assmus B, Urbich C, Aicher A. et al. HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circulation Res 2003; 92: 1049-1055.
  CrossrefPubMedGoogle Scholar
• 98 Shantsila E, Watson T, Lip GY. Endothelial progenitor cells in cardiovascular disorders. J Am Coll Cardiol 2007; 49: 741-752.
  CrossrefPubMedGoogle Scholar
• 99 Pistrosch F, Herbrig K, Oelschlaegel U. et al. PPARgamma-agonist rosiglitazone increases number and migratory activity of cultured endothelial progenitor cells. Atherosclerosis 2005; 183: 163-167.
  CrossrefPubMedGoogle Scholar
• 100 Wang CH, Ting MK, Verma S. et al. Pioglitazone increases the numbers and improves the functional capacity of endothelial progenitor cells in patients with diabetes mellitus. Am Heart J 2006; 152: 1051-1058.
  PubMedGoogle Scholar
• 101 Di Stefano R, Barsotti MC, Melillo E. et al. The prostacyclin analogue iloprost increases circulating endothelial progenitor cells in patients with critical limb ischemia. Thromb Haemost 2008; 100: 871-877.
  Article in Thieme ConnectPubMedGoogle Scholar
• 102 Wadhwa M, Thorpe R. Haematopoietic growth factors and their therapeutic use. Thromb Haemost 2008; 99: 863-873.
  Article in Thieme ConnectPubMedGoogle Scholar
• 103 Akita T, Murohara T, Ikeda H. et al. Hypoxic preconditioning augments efficacy of human endothelial progenitor cells for therapeutic neovascularization. Lab Invest 2003; 83: 65-73.
  CrossrefPubMedGoogle Scholar
• 104 Sasaki K, Heeschen C, Aicher A. et al. Ex vivo pretreatment of bone marrow mononuclear cells with endothelial NO synthase enhancer AVE9488 enhances their functional activity for cell therapy. Proc Natl Acad Sci USA 2006; 103: 14537-14541.
  CrossrefPubMedGoogle Scholar
• 105 Iwaguro H, Yamaguchi J, Kalka C. et al. Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation 2002; 105: 732-738.
  CrossrefPubMedGoogle Scholar
• 106 Yi C, Xia W, Zheng Y. et al. Transplantation of endothelial progenitor cells transferred by vascular endothelial growth factor gene for vascular regeneration of ischemic flaps. J Surg Res 2006; 135: 100-106.
  CrossrefPubMedGoogle Scholar
• 107 Choi JH, Hur J, Yoon CH. et al. Augmentation of therapeutic angiogenesis using genetically modified human endothelial progenitor cells with altered glycogen synthase kinase-3beta activity. J Biol Chem 2004; 279: 49430-49438.
  CrossrefPubMedGoogle Scholar
• 108 Miyamoto K, Nishigami K, Nagaya N. et al. Unblinded pilot study of autologous transplantation of bone marrow mononuclear cells in patients with thromboangiitis obliterans. Circulation 2006; 114: 2679-2684.
  CrossrefPubMedGoogle Scholar
• 109 Matoba S, Tatsumi T, Murohara T. et al. Long-term clinical outcome after intramuscular implantation of bone marrow mononuclear cells (Therapeutic Angio-genesis by Cell Transplantation [TACT] trial) in patients with chronic limb ischemia. Am Heart J 2008; 156: 1010-1018.
  CrossrefPubMedGoogle Scholar
• 110 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.
  CrossrefPubMedGoogle Scholar
• 111 Kinnaird T, Stabile E, Burnett MS. et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 2004; 109: 1543-1549.
  CrossrefPubMedGoogle Scholar
• 112 Kinnaird T, Stabile E, Burnett MS. et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circulation Res 2004; 94: 678-685.
  CrossrefPubMedGoogle Scholar
• 113 Niagara MI, Haider HK, Ye L. et al. Autologous skeletal myoblasts transduced with a new adenoviral bicistronic vector for treatment of hind limb ischemia. J Vasc Surg 2004; 40: 774-785.
  CrossrefPubMedGoogle Scholar
• 114 Napoli C, Williams-Ignarro S, de Nigris F. et al. Beneficial effects of concurrent autologous bone marrow cell therapy and metabolic intervention in ischemia-induced angiogenesis in the mouse hindlimb. Proc Natl Acad Sci USA 2005; 102: 17202-17206.
  CrossrefPubMedGoogle Scholar
• 115 Takagi Y, Omura T, Yoshiyama M. et al. Granulocyte-colony stimulating factor augments neovascularization induced by bone marrow transplantation in rat hindlimb ischemia. J Pharmacol Sci 2005; 99: 45-51.
  CrossrefPubMedGoogle Scholar
• 116 Iwase T, Nagaya N, Fujii T. et al. Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia. Cardiovasc Res 2005; 66: 543-551.
  CrossrefPubMedGoogle Scholar
• 117 Nakagami H, Maeda K, Morishita R. et al. Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells. Arterioscler Thromb Vasc Biol 2005; 25: 2542-2547.
  CrossrefPubMedGoogle Scholar
• 118 Yoon KH, Lee JH, Kim JW. et al. Epidemic obesity and type 2 diabetes in Asia. Lancet 2006; 368: 1681-1688.
  CrossrefPubMedGoogle Scholar
• 119 Aicher A, Heeschen C, Sasaki K. et al. Low-energy shock wave for enhancing recruitment of endothelial progenitor cells: a new modality to increase efficacy of cell therapy in chronic hind limb ischemia. Circulation 2006; 114: 2823-2830.
  CrossrefPubMedGoogle Scholar
• 120 Awad O, Dedkov EI, Jiao C. et al. Differential healing activities of CD34+ and CD14+ endothelial cell progenitors. Arterioscler Thromb Vasc Biol 2006; 26: 758-764.
  CrossrefPubMedGoogle Scholar
• 121 Kobayashi K, Kondo T, Inoue N. et al. Combination of in vivo angiopoietin-1 gene transfer and autologous bone marrow cell implantation for functional therapeutic angiogenesis. Arterioscler Thromb Vasc Biol 2006; 26: 1465-1472.
  CrossrefPubMedGoogle Scholar
• 122 Li S, Zhou B, Han ZC. Therapeutic neovascularization by transplantation of mobilized peripheral blood mononuclear cells for limb ischemia. A comparison between CD34+ and. Thromb Haemost 2006; 95: 301-311.
  Article in Thieme ConnectPubMedGoogle Scholar
• 123 Kim SW, Han H, Chae GT. et al. Successful stem cell therapy using umbilical cord blood-derived multipotent stem cells for Buerger’s disease and ischemic limb disease animal model. Stem Cells 2006; 24: 1620-1626.
  CrossrefPubMedGoogle Scholar
• 124 Moon MH, Kim SY, Kim YJ. et al. Human adipose tissue-derived mesenchymal stem cells improve postnatal neovascularization in a mouse model of hindlimb ischemia. Cell Physiol Biochem 2006; 17: 279-290.
  CrossrefPubMedGoogle Scholar
• 125 Sica V, Williams-Ignarro S, de Nigris F. et al. Autologous bone marrow cell therapy and metabolic intervention in ischemia-induced angiogenesis in the diabetic mouse hindlimb. Cell Cycle 2006; 05: 2903-2908.
  CrossrefPubMedGoogle Scholar
• 126 Jeon O, Song SJ, Bhang SH. et al. Additive effect of endothelial progenitor cell mobilization and bone marrow mononuclear cell transplantation on angiogenesis in mouse ischemic limbs. J Biomed Sci 2007; 14: 323-330.
  CrossrefPubMedGoogle Scholar
• 127 Zhang H, Zhang N, Li M. et al. Therapeutic angiogenesis of bone marrow mono-nuclear cells (MNCs) and peripheral blood MNCs: transplantation for ischemic hindlimb. Ann Vasc Surg 2008; 22: 238-247.
  CrossrefPubMedGoogle Scholar
• 128 Esato K, Hamano K, Li TS. et al. Neovascularization induced by autologous bone marrow cell implantation in peripheral arterial disease. Cell Transplant 2002; 11: 747-752.
  CrossrefPubMedGoogle Scholar
• 129 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.
  CrossrefPubMedGoogle Scholar
• 130 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.
  CrossrefPubMedGoogle Scholar
• 131 Miyamoto M, Yasutake M, Takano H. et al. Therapeutic angiogenesis by autologous bone marrow cell implantation for refractory chronic peripheral arterial disease using assessment of neovascularization by 99mTc-tetrofosmin (TF) per-fusion scintigraphy. Cell Transplant 2004; 13: 429-437.
  CrossrefPubMedGoogle Scholar
• 132 Nizankowski R, Petriczek T, Skotnicki A. et al. The treatment of advanced chronic lower limb ischaemia with marrow stem cell autotransplantation. Kardiol Pol 2005; 63: 351-360.
  PubMedGoogle Scholar
• 133 Durdu S, Akar AR, Arat M. et al. Autologous bone-marrow mononuclear cell implantation for patients with Rutherford grade II-III thromboangiitis obliterans. J Vasc Surg 2006; 44: 732-739.
  CrossrefPubMedGoogle Scholar
• 134 Bartsch T, Falke T, Brehm M. et al. Transplantation of autologous adult bone marrow stem cells in patients with severe peripheral arterial occlusion disease. Med Klin (Munich) 2006; 101 (Suppl. 01) 195-197.
  PubMedGoogle Scholar
• 135 Kajiguchi M, Kondo T, Izawa H. 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.
  CrossrefPubMedGoogle Scholar
• 136 Huang PP, Yang XF, Li SZ. et al. 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. Thromb Haemost 2007; 98: 1335-1342.
  Article in Thieme ConnectPubMedGoogle Scholar
• 137 Hernandez P, Cortina L, Artaza H. 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.
  CrossrefPubMedGoogle Scholar
• 138 Gu YQ, Zhang J, Guo LR. et al. Transplantation of autologous bone marrow mononuclear cells for patients with lower limb ischemia. Chin Med J (Engl) 2008; 121: 963-967.
  PubMedGoogle Scholar
• 139 Chochola M, Pytlik R, Kobylka P. et al. Autologous intra-arterial infusion of bone marrow mononuclear cells in patients with critical leg ischemia. Int Angiol 2008; 27: 281-290.
  PubMedGoogle Scholar
• 140 Wester T, Jorgensen JJ, Stranden E. et al. Treatment with autologous bone marrow mononuclear cells in patients with critical lower limb ischaemia. A pilot study. Scand J Surg 2008; 97: 56-62.
  CrossrefPubMedGoogle Scholar
• 141 Van Tongeren RB, Hamming JF, Fibbe WE. et al. Intramuscular or combined intramuscular/intra-arterial administration of bone marrow mononuclear cells: a clinical trial in patients with advanced limb ischemia. J Cardiovasc Surg 2008; 49: 51-58.
  PubMedGoogle Scholar
• 142 De Vriese AS, Billiet J, Van Droogenbroeck J. et al. Autologous transplantation of bone marrow mononuclear cells for limb ischemia in a caucasian population with atherosclerosis obliterans. J Intern Med 2008; 263: 395-403.
  CrossrefPubMedGoogle Scholar
• 143 Amann B, Luedemann C, Ratei R. et al. Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease. Cell Transplant 2009; 18: 371-380.
  CrossrefPubMedGoogle Scholar
• 144 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.
  Article in Thieme ConnectPubMedGoogle Scholar
• 145 Kawamura A, Horie T, Tsuda I. et al. Prevention of limb amputation in patients with limbs ulcers by autologous peripheral blood mononuclear cell implantation. Ther Apher Dial 2005; 09: 59-63.
  CrossrefPubMedGoogle Scholar
• 146 Lenk K, Adams V, Lurz P. 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.
  CrossrefPubMedGoogle Scholar
• 147 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: 2155-2160.
  CrossrefPubMedGoogle Scholar
• 148 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.
  CrossrefPubMedGoogle Scholar
• 149 Kawamura A, Horie T, Tsuda I. 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; 09: 226-233.
  CrossrefPubMedGoogle Scholar