Emerging hurdles in stem cell therapy for peripheral vascular disease

  • Xabier L. Aranguren
  • Catherine M. Verfaillie
  • Aernout Luttun


Peripheral vascular disease (PVD) is a growing medical problem in Western societies and presents itself mainly in two different clinical forms. Intermittent claudication is an early moderate manifestation, while patients with critical limb ischemia suffer from severe muscle tissue loss or ulcers and are at high risk for limb amputation. Unfortunately, many patients cannot be helped with currently available surgical or endovascular revascularization procedures because of the complex anatomy of the vascular occlusion and/or the presence of other risk factors. Noninvasive stem cell therapy has been proposed as an alternative for such patients. Although pioneering clinical experience with stem cell-related therapy seems promising, it is too early for general clinical use of this technique, since many questions remain unanswered. Indeed, while questions about safety, dose, and administration route/timing/frequency are the first ones to be addressed when designing a stem cell-based clinical approach, there is accumulating evidence from recent (pre-)clinical studies that other issues may also be at stake. For instance, the choice of stem cells to be used and its precise mechanism of action, the need/possibility for concurrent tissue regeneration in case of irreversible tissue loss, the differentiation degree and specific vascular identity of the transplanted cells, and the long-term survival of engrafted cells in the absence of a normal supportive tissue environment should be well considered. Here, rather than presenting a comprehensive and extensive overview on the current literature on stem/progenitor cells and revascularization, we highlight some of the outstanding issues emerging from the recent (pre-)clinical literature that may codetermine the successful application of stem cells in a wide range of PVD patients in the future.


Vascular disease Stem cells Clinical research Regeneration Ischemia Endothelium 


  1. 1.
    Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, Bell K, Caporusso J, Durand-Zaleski I, Komori K, Lammer J, Liapis C, Novo S, Razavi M, Robbs J, Schaper N, Shigematsu H, Sapoval M, White C, White J (2007) Inter-society consensus for the management of peripheral arterial disease (TASC II). Eur J Vasc Endovasc Surg 33(Suppl 1):S1–S75PubMedGoogle Scholar
  2. 2.
    Durdu S, Akar AR, Arat M, Sancak T, Eren NT, Ozyurda U (2006) Autologous bone-marrow mononuclear cell implantation for patients with Rutherford grade II–III thromboangiitis obliterans. J Vasc Surg 44:732–739PubMedGoogle Scholar
  3. 3.
    Tateno K, Minamino T, Toko H, Akazawa H, Shimizu N, Takeda S, Kunieda T, Miyauchi H, Oyama T, Matsuura K, Nishi J, Kobayashi Y, Nagai T, Kuwabara Y, Iwakura Y, Nomura F, Saito Y, Komuro I (2006) Critical roles of muscle-secreted angiogenic factors in therapeutic neovascularization. Circ Res 98:1194–1202PubMedGoogle Scholar
  4. 4.
    Collinson DJ, Donnelly R (2004) Therapeutic angiogenesis in peripheral arterial disease: can biotechnology produce an effective collateral circulation? Eur J Vasc Endovasc Surg 28:9–23PubMedGoogle Scholar
  5. 5.
    Nikol S, Baumgartner I, Van Belle E, Diehm C, Visona A, Capogrossi MC, Ferreira-Maldent N, Gallino A, Wyatt MG, Wijesinghe LD, Fusari M, Stephan D, Emmerich J, Pompilio G, Vermassen F, Pham E, Grek V, Coleman M, Meyer F (2008) Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther 16:972–978PubMedGoogle Scholar
  6. 6.
    Vincent KA, Feron O, Kelly RA (2002) Harnessing the response to tissue hypoxia: HIF-1 alpha and therapeutic angiogenesis. Trends Cardiovasc Med 12:362–367PubMedGoogle Scholar
  7. 7.
    Carmeliet P, Baes M (2008) Metabolism and therapeutic angiogenesis. N Engl J Med 358:2511–2512PubMedGoogle Scholar
  8. 8.
    Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967PubMedGoogle Scholar
  9. 9.
    Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, Amano K, Kishimoto Y, Yoshimoto K, Akashi H, Shimada K, Iwasaka T, Imaizumi T (2002) Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 360:427–435PubMedGoogle Scholar
  10. 10.
    Kim SW, Han H, Chae GT, Lee SH, Bo S, Yoon JH, Lee YS, Lee KS, Park HK, Kang KS (2006) Successful stem cell therapy using umbilical cord blood-derived multipotent stem cells for Buerger's disease and ischemic limb disease animal model. Stem Cells 24:1620–1626PubMedGoogle Scholar
  11. 11.
    Kamata Y, Takahashi Y, Iwamoto M, Matsui K, Murakami Y, Muroi K, Ikeda U, Shimada K, Yoshio T, Okazaki H, Minota S (2007) Local implantation of autologous mononuclear cells from bone marrow and peripheral blood for treatment of ischaemic digits in patients with connective tissue diseases. Rheumatology (Oxford) 46:882–884Google Scholar
  12. 12.
    Miyamoto K, Nishigami K, Nagaya N, Akutsu K, Chiku M, Kamei M, Soma T, Miyata S, Higashi M, Tanaka R, Nakatani T, Nonogi H, Takeshita S (2006) Unblinded pilot study of autologous transplantation of bone marrow mononuclear cells in patients with thromboangiitis obliterans. Circulation 114:2679–2684PubMedGoogle Scholar
  13. 13.
    De Vriese AS, Billiet J, Van Droogenbroeck J, Ghekiere J, De Letter JA (2008) Autologous transplantation of bone marrow mononuclear cells for limb ischemia in a Caucasian population with atherosclerosis obliterans. J Intern Med 263:395–403PubMedGoogle Scholar
  14. 14.
    Chen JZ, Zhang FR, Tao QM, Wang XX, Zhu JH, Zhu JH (2004) Number and activity of endothelial progenitor cells from peripheral blood in patients with hypercholesterolaemia. Clin Sci (Lond) 107:273–280CrossRefGoogle Scholar
  15. 15.
    Dimmeler S, Vasa-Nicotera M (2003) Aging of progenitor cells: limitation for regenerative capacity? J Am Coll Cardiol 42:2081–2082PubMedGoogle Scholar
  16. 16.
    Michaud SE, Dussault S, Haddad P, Groleau J, Rivard A (2006) Circulating endothelial progenitor cells from healthy smokers exhibit impaired functional activities. Atherosclerosis 187:423–432PubMedGoogle Scholar
  17. 17.
    Oliveras A, Soler MJ, Martinez-Estrada OM, Vazquez S, Marco-Feliu D, Vila JS, Vilaro S, Lloveras J (2008) Endothelial progenitor cells are reduced in refractory hypertension. J Hum Hypertens 22:183–190PubMedGoogle Scholar
  18. 18.
    Scheubel RJ, Kahrstedt S, Weber H, Holtz J, Friedrich I, Borgermann J, Silber RE, Simm A (2006) Depression of progenitor cell function by advanced glycation endproducts (AGEs): potential relevance for impaired angiogenesis in advanced age and diabetes. Exp Gerontol 41:540–548PubMedGoogle Scholar
  19. 19.
    Honold J, Lehmann R, Heeschen C, Walter DH, Assmus B, Sasaki K, Martin H, Haendeler J, Zeiher AM, Dimmeler S (2006) Effects of granulocyte colony simulating factor on functional activities of endothelial progenitor cells in patients with chronic ischemic heart disease. Arterioscler Thromb Vasc Biol 26:2238–2243PubMedGoogle Scholar
  20. 20.
    Waters RE, Terjung RL, Peters KG, Annex BH (2004) Preclinical models of human peripheral arterial occlusive disease: implications for investigation of therapeutic agents. J Appl Physiol 97:773–780PubMedGoogle Scholar
  21. 21.
    Tang GL, Chang DS, Sarkar R, Wang R, Messina LM (2005) The effect of gradual or acute arterial occlusion on skeletal muscle blood flow, arteriogenesis, and inflammation in rat hindlimb ischemia. J Vasc Surg 41:312–320PubMedGoogle Scholar
  22. 22.
    Aranguren XL, McCue JD, Hendrickx B, Zhu XH, Du F, Chen E, Pelacho B, Penuelas I, Abizanda G, Uriz M, Frommer SA, Ross JJ, Schroeder BA, Seaborn MS, Adney JR, Hagenbrock J, Harris NH, Zhang Y, Zhang X, Nelson-Holte MH, Jiang Y, Billiau AD, Chen W, Prosper F, Verfaillie CM, Luttun A (2008) Multipotent adult progenitor cells sustain function of ischemic limbs in mice. J Clin Invest 118:505–514PubMedGoogle Scholar
  23. 23.
    Helisch A, Wagner S, Khan N, Drinane M, Wolfram S, Heil M, Ziegelhoeffer T, Brandt U, Pearlman JD, Swartz HM, Schaper W (2006) Impact of mouse strain differences in innate hindlimb collateral vasculature. Arterioscler Thromb Vasc Biol 26:520–526PubMedGoogle Scholar
  24. 24.
    Li Z, Wu JC, Sheikh AY, Kraft D, Cao F, Xie X, Patel M, Gambhir SS, Robbins RC, Cooke JP, Wu JC (2007) Differentiation, survival, and function of embryonic stem cell derived endothelial cells for ischemic heart disease. Circulation 116:I46–54PubMedGoogle Scholar
  25. 25.
    Cho SW, Moon SH, Lee SH, Kang SW, Kim J, Lim JM, Kim HS, Kim BS, Chung HM (2007) Improvement of postnatal neovascularization by human embryonic stem cell derived endothelial-like cell transplantation in a mouse model of hindlimb ischemia. Circulation 116:2409–2419PubMedGoogle Scholar
  26. 26.
    Kupatt C, Horstkotte J, Vlastos GA, Pfosser A, Lebherz C, Semisch M, Thalgott M, Buttner K, Browarzyk C, Mages J, Hoffmann R, Deten A, Lamparter M, Muller F, Beck H, Buning H, Boekstegers P, Hatzopoulos AK (2005) Embryonic endothelial progenitor cells expressing a broad range of proangiogenic and remodeling factors enhance vascularization and tissue recovery in acute and chronic ischemia. Faseb J 19:1576–1578PubMedGoogle Scholar
  27. 27.
    Sone M, Itoh H, Yamahara K, Yamashita JK, Yurugi-Kobayashi T, Nonoguchi A, Suzuki Y, Chao TH, Sawada N, Fukunaga Y, Miyashita K, Park K, Oyamada N, Sawada N, Taura D, Tamura N, Kondo Y, Nito S, Suemori H, Nakatsuji N, Nishikawa S, Nakao K (2007) Pathway for differentiation of human embryonic stem cells to vascular cell components and their potential for vascular regeneration. Arterioscler Thromb Vasc Biol 27:2127–2134PubMedGoogle Scholar
  28. 28.
    Yamahara K, Sone M, Itoh H, Yamashita JK, Yurugi-Kobayashi T, Homma K, Chao TH, Miyashita K, Park K, Oyamada N, Sawada N, Taura D, Fukunaga Y, Tamura N, Nakao K (2008) Augmentation of neovascularization in hindlimb ischemia by combined transplantation of human embryonic stem cells-derived endothelial and mural cells. PLoS ONE 3:e1666PubMedGoogle Scholar
  29. 29.
    Lu SJ, Feng Q, Caballero S, Chen Y, Moore MA, Grant MB, Lanza R (2007) Generation of functional hemangioblasts from human embryonic stem cells. Nat Methods 4:501–509PubMedGoogle Scholar
  30. 30.
    Di Rocco G, Iachininoto MG, Tritarelli A, Straino S, Zacheo A, Germani A, Crea F, Capogrossi MC (2006) Myogenic potential of adipose-tissue-derived cells. J Cell Sci 119:2945–2952PubMedGoogle Scholar
  31. 31.
    Huss R, Heil M, Moosmann S, Ziegelhoeffer T, Sagebiel S, Seliger C, Kinston S, Gottgens B (2004) Improved arteriogenesis with simultaneous skeletal muscle repair in ischemic tissue by SCL(+) multipotent adult progenitor cell clones from peripheral blood. J Vasc Res 41:422–431PubMedGoogle Scholar
  32. 32.
    Invernici G, Emanueli C, Madeddu P, Cristini S, Gadau S, Benetti A, Ciusani E, Stassi G, Siragusa M, Nicosia R, Peschle C, Fascio U, Colombo A, Rizzuti T, Parati E, Alessandri G (2007) Human fetal aorta contains vascular progenitor cells capable of inducing vasculogenesis, angiogenesis, and myogenesis in vitro and in a murine model of peripheral ischemia. Am J Pathol 170:1879–1892PubMedGoogle Scholar
  33. 33.
    Madeddu P, Emanueli C, Pelosi E, Salis MB, Cerio AM, Bonanno G, Patti M, Stassi G, Condorelli G, Peschle C (2004) Transplantation of low dose CD34+KDR+ cells promotes vascular and muscular regeneration in ischemic limbs. Faseb J 18:1737–1739PubMedGoogle Scholar
  34. 34.
    Pesce M, Orlandi A, Iachininoto MG, Straino S, Torella AR, Rizzuti V, Pompilio G, Bonanno G, Scambia G, Capogrossi MC (2003) Myoendothelial differentiation of human umbilical cord blood-derived stem cells in ischemic limb tissues. Circ Res 93:e51–62PubMedGoogle Scholar
  35. 35.
    Moon MH, Kim SY, Kim YJ, Kim SJ, Lee JB, Bae YC, Sung SM, Jung JS (2006) Human adipose tissue-derived mesenchymal stem cells improve postnatal neovascularization in a mouse model of hindlimb ischemia. Cell Physiol Biochem 17:279–290PubMedGoogle Scholar
  36. 36.
    Nakagami H, Maeda K, Morishita R, Iguchi S, Nishikawa T, Takami Y, Kikuchi Y, Saito Y, Tamai K, Ogihara T, Kaneda Y (2005) Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells. Arterioscler Thromb Vasc Biol 25:2542–2547PubMedGoogle Scholar
  37. 37.
    Luttun A, Verfaillie CM (2007) Will the real EPC please stand up? Blood 109:1795–1796Google Scholar
  38. 38.
    Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F, Krasich R, Temm CJ, Prchal JT, Ingram DA (2007) Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 109:1801–1809PubMedGoogle Scholar
  39. 39.
    Yoon CH, Hur J, Park KW, Kim JH, Lee CS, Oh IY, Kim TY, Cho HJ, Kang HJ, Chae IH, Yang HK, Oh BH, Park YB, Kim HS (2005) Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases. Circulation 112:1618–1627PubMedGoogle Scholar
  40. 40.
    Iwase T, Nagaya N, Fujii T, Itoh T, Murakami S, Matsumoto T, Kangawa K, Kitamura S (2005) Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia. Cardiovasc Res 66:543–551PubMedGoogle Scholar
  41. 41.
    Planat-Benard V, Silvestre JS, Cousin B, Andre M, Nibbelink M, Tamarat R, Clergue M, Manneville C, Saillan-Barreau C, Duriez M, Tedgui A, Levy B, Penicaud L, Casteilla L (2004) Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation 109:656–663PubMedGoogle Scholar
  42. 42.
    Awad O, Dedkov EI, Jiao C, Bloomer S, Tomanek RJ, Schatteman GC (2006) Differential healing activities of CD34+ and CD14+ endothelial cell progenitors. Arterioscler Thromb Vasc Biol 26:758–764PubMedGoogle Scholar
  43. 43.
    Li TS, Hamano K, Nishida M, Hayashi M, Ito H, Mikamo A, Matsuzaki M (2003) CD117+ stem cells play a key role in therapeutic angiogenesis induced by bone marrow cell implantation. Am J Physiol Heart Circ Physiol 285:H931–937PubMedGoogle Scholar
  44. 44.
    Urbich C, Heeschen C, Aicher A, Dernbach E, Zeiher AM, Dimmeler S (2003) Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells. Circulation 108:2511–2516PubMedGoogle Scholar
  45. 45.
    Finney MR, Greco NJ, Haynesworth SE, Martin JM, Hedrick DP, Swan JZ, Winter DG, Kadereit S, Joseph ME, Fu P, Pompili VJ, Laughlin MJ (2006) 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 12:585–593PubMedGoogle Scholar
  46. 46.
    Iba O, Matsubara H, Nozawa Y, Fujiyama S, Amano K, Mori Y, Kojima H, Iwasaka T (2002) Angiogenesis by implantation of peripheral blood mononuclear cells and platelets into ischemic limbs. Circulation 106:2019–2025PubMedGoogle Scholar
  47. 47.
    Ozawa T, Toba K, Kato K, Minagawa S, Saigawa T, Hanawa H, Makiyama Y, Moriyama M, Honma K, Isoda M, Hasegawa G, Naito M, Takahashi M, Aizawa Y (2006) Erythroid cells play essential roles in angiogenesis by bone marrow cell implantation. J Mol Cell Cardiol 40:629–638PubMedGoogle Scholar
  48. 48.
    Kawamoto A, Iwasaki H, Kusano K, Murayama T, Oyamada A, Silver M, Hulbert C, Gavin M, Hanley A, Ma H, Kearney M, Zak V, Asahara T, Losordo DW (2006) CD34-positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells. Circulation 114:2163–2169PubMedGoogle Scholar
  49. 49.
    Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S, Fuchs S, Epstein SE (2004) Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 109:1543–1549PubMedGoogle Scholar
  50. 50.
    Bailey AS, Willenbring H, Jiang S, Anderson DA, Schroeder DA, Wong MH, Grompe M, Fleming WH (2006) Myeloid lineage progenitors give rise to vascular endothelium. Proc Natl Acad Sci U S A 103:13156–13161PubMedGoogle Scholar
  51. 51.
    Heil M, Schaper W (2004) Pathophysiology of collateral development. Coron Artery Dis 15:373–378PubMedGoogle Scholar
  52. 52.
    Nishiyama K, Takaji K, Kataoka K, Kurihara Y, Yoshimura M, Kato A, Ogawa H, Kurihara H (2005) Id1 gene transfer confers angiogenic property on fully differentiated endothelial cells and contributes to therapeutic angiogenesis. Circulation 112:2840–2850PubMedGoogle Scholar
  53. 53.
    Urbich C, Heeschen C, Aicher A, Sasaki K, Bruhl T, Farhadi MR, Vajkoczy P, Hofmann WK, Peters C, Pennacchio LA, Abolmaali ND, Chavakis E, Reinheckel T, Zeiher AM, Dimmeler S (2005) Cathepsin L is required for endothelial progenitor cell-induced neovascularization. Nat Med 11:206–213PubMedGoogle Scholar
  54. 54.
    Lanner F, Sohl M, Farnebo F (2007) Functional arterial and venous fate is determined by graded VEGF signaling and notch status during embryonic stem cell differentiation. Arterioscler Thromb Vasc Biol 27:487–493PubMedGoogle Scholar
  55. 55.
    Yurugi-Kobayashi T, Itoh H, Schroeder T, Nakano A, Narazaki G, Kita F, Yanagi K, Hiraoka-Kanie M, Inoue E, Ara T, Nagasawa T, Just U, Nakao K, Nishikawa S, Yamashita JK (2006) Adrenomedullin/cyclic AMP pathway induces Notch activation and differentiation of arterial endothelial cells from vascular progenitors. Arterioscler Thromb Vasc Biol 26:1977–1984PubMedGoogle Scholar
  56. 56.
    Aranguren XL, Luttun A, Clavel C, Moreno C, Abizanda G, Barajas MA, Pelacho B, Uriz M, Arana M, Echavarri A, Soriano M, Andreu EJ, Merino J, Garcia-Verdugo JM, Verfaillie CM, Prosper F (2007) In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells. Blood 109:2634–2642PubMedGoogle Scholar
  57. 57.
    Chavakis E, Aicher A, Heeschen C, Sasaki K, Kaiser R, El Makhfi N, Urbich C, Peters T, Scharffetter-Kochanek K, Zeiher AM, Chavakis T, Dimmeler S (2005) Role of beta2-integrins for homing and neovascularization capacity of endothelial progenitor cells. J Exp Med 201:63–72PubMedGoogle Scholar
  58. 58.
    Cho HJ, Youn SW, Cheon SI, Kim TY, Hur J, Zhang SY, Lee SP, Park KW, Lee MM, Choi YS, Park YB, Kim HS (2005) Regulation of endothelial cell and endothelial progenitor cell survival and vasculogenesis by integrin-linked kinase. Arterioscler Thromb Vasc Biol 25:1154–1160PubMedGoogle Scholar
  59. 59.
    Choi JH, Hur J, Yoon CH, Kim JH, Lee CS, Youn SW, Oh IY, Skurk C, Murohara T, Park YB, Walsh K, Kim HS (2004) Augmentation of therapeutic angiogenesis using genetically modified human endothelial progenitor cells with altered glycogen synthase kinase-3beta activity. J Biol Chem 279:49430–49438PubMedGoogle Scholar
  60. 60.
    Iwaguro H, Yamaguchi J, Kalka C, Murasawa S, Masuda H, Hayashi S, Silver M, Li T, Isner JM, Asahara T (2002) Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation 105:732–738PubMedGoogle Scholar
  61. 61.
    Jeon O, Kang SW, Lim HW, Choi D, Kim DI, Lee SH, Chung JH, Kim BS (2006) Synergistic effect of sustained delivery of basic fibroblast growth factor and bone marrow mononuclear cell transplantation on angiogenesis in mouse ischemic limbs. Biomaterials 27:1617–1625PubMedGoogle Scholar
  62. 62.
    Jiang M, Wang B, Wang C, He B, Fan H, Guo TB, Shao Q, Gao L, Liu Y (2008) Angiogenesis by transplantation of HIF-1 alpha modified EPCs into ischemic limbs. J Cell Biochem 103:321–334PubMedGoogle Scholar
  63. 63.
    Kong D, Melo LG, Mangi AA, Zhang L, Lopez-Ilasaca M, Perrella MA, Liew CC, Pratt RE, Dzau VJ (2004) Enhanced inhibition of neointimal hyperplasia by genetically engineered endothelial progenitor cells. Circulation 109:1769–1775PubMedGoogle Scholar
  64. 64.
    Li TS, Hamano K, Suzuki K, Ito H, Zempo N, Matsuzaki M (2002) Improved angiogenic potency by implantation of ex vivo hypoxia prestimulated bone marrow cells in rats. Am J Physiol Heart Circ Physiol 283:H468–473PubMedGoogle Scholar
  65. 65.
    Murasawa S, Llevadot J, Silver M, Isner JM, Losordo DW, Asahara T (2002) Constitutive human telomerase reverse transcriptase expression enhances regenerative properties of endothelial progenitor cells. Circulation 106:1133–1139PubMedGoogle Scholar
  66. 66.
    Sasaki K, Heeschen C, Aicher A, Ziebart T, Honold J, Urbich C, Rossig L, Koehl U, Koyanagi M, Mohamed A, Brandes RP, Martin H, Zeiher AM, Dimmeler S (2006) 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 U S A 103:14537–14541PubMedGoogle Scholar
  67. 67.
    Walter DH, Rochwalsky U, Reinhold J, Seeger F, Aicher A, Urbich C, Spyridopoulos I, Chun J, Brinkmann V, Keul P, Levkau B, Zeiher AM, Dimmeler S, Haendeler J (2007) Sphingosine-1-phosphate stimulates the functional capacity of progenitor cells by activation of the CXCR4-dependent signaling pathway via the S1P3 receptor. Arterioscler Thromb Vasc Biol 27:275–282PubMedGoogle Scholar
  68. 68.
    Akasaki Y, Miyata M, Eto H, Shirasawa T, Hamada N, Ikeda Y, Biro S, Otsuji Y, Tei C (2006) Repeated thermal therapy up-regulates endothelial nitric oxide synthase and augments angiogenesis in a mouse model of hindlimb ischemia. Circ J 70:463–470PubMedGoogle Scholar
  69. 69.
    Asano T, Kaneko E, Shinozaki S, Imai Y, Shibayama M, Chiba T, Ai M, Kawakami A, Asaoka H, Nakayama T, Mano Y, Shimokado K (2007) Hyperbaric oxygen induces basic fibroblast growth factor and hepatocyte growth factor expression, and enhances blood perfusion and muscle regeneration in mouse ischemic hind limbs. Circ J 71:405–411PubMedGoogle Scholar
  70. 70.
    Heissig B, Rafii S, Akiyama H, Ohki Y, Sato Y, Rafael T, Zhu Z, Hicklin DJ, Okumura K, Ogawa H, Werb Z, Hattori K (2005) Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization. J Exp Med 202:739–750PubMedGoogle Scholar
  71. 71.
    Bartsch T, Brehm M, Zeus T, Kogler G, Wernet P, Strauer BE (2007) Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (the TAM-PAD study). Clin Res Cardiol 96:891–899PubMedGoogle Scholar
  72. 72.
    de Nigris F, Balestrieri ML, Williams-Ignarro S, D'Armiento FP, Lerman LO, Byrns R, Crimi E, Palagiano A, Fatigati G, Ignarro LJ, Napoli C (2007) Therapeutic effects of autologous bone marrow cells and metabolic intervention in the ischemic hindlimb of spontaneously hypertensive rats involve reduced cell senescence and CXCR4/Akt/eNOS pathways. J Cardiovasc Pharmacol 50:424–433PubMedGoogle Scholar
  73. 73.
    Hu Z, Zhang F, Yang Z, Yang N, Zhang D, Zhang J, Cao K (2008) Combination of simvastatin administration and EPC transplantation enhances angiogenesis and protects against apoptosis for hindlimb ischemia. J Biomed Sci 15:509–517 Mar 8PubMedGoogle Scholar
  74. 74.
    Jeon O, Song SJ, Bhang SH, Choi CY, Kim MJ, Kim BS (2007) Additive effect of endothelial progenitor cell mobilization and bone marrow mononuclear cell transplantation on angiogenesis in mouse ischemic limbs. J Biomed Sci 14:323–330PubMedGoogle Scholar
  75. 75.
    Kobayashi K, Kondo T, Inoue N, Aoki M, Mizuno M, Komori K, Yoshida J, Murohara T (2006) Combination of in vivo angiopoietin-1 gene transfer and autologous bone marrow cell implantation for functional therapeutic angiogenesis. Arterioscler Thromb Vasc Biol 26:1465–1472PubMedGoogle Scholar
  76. 76.
    Suuronen EJ, Veinot JP, Wong S, Kapila V, Price J, Griffith M, Mesana TG, Ruel M (2006) Tissue-engineered injectable collagen-based matrices for improved cell delivery and vascularization of ischemic tissue using CD133+ progenitors expanded from the peripheral blood. Circulation 114:I138–144PubMedGoogle Scholar
  77. 77.
    Esato K, Hamano K, Li TS, Furutani A, Seyama A, Takenaka H, Zempo N (2002) Neovascularization induced by autologous bone marrow cell implantation in peripheral arterial disease. Cell Transplant 11:747–752PubMedGoogle Scholar
  78. 78.
    Saigawa T, Kato K, Ozawa T, Toba K, Makiyama Y, Minagawa S, Hashimoto S, Furukawa T, Nakamura Y, Hanawa H, Kodama M, Yoshimura N, Fujiwara H, Namura O, Sogawa M, Hayashi J, Aizawa Y (2004) 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 68:1189–1193PubMedGoogle Scholar
  79. 79.
    Higashi Y, Kimura M, Hara K, Noma K, Jitsuiki D, Nakagawa K, Oshima T, Chayama K, Sueda T, Goto C, Matsubara H, Murohara T, Yoshizumi M (2004) Autologous bone-marrow mononuclear cell implantation improves endothelium-dependent vasodilation in patients with limb ischemia. Circulation 109:1215–1218PubMedGoogle Scholar
  80. 80.
    Miyamoto M, Yasutake M, Takano H, Takagi H, Takagi G, Mizuno H, Kumita S, Takano T (2004) Therapeutic angiogenesis by autologous bone marrow cell implantation for refractory chronic peripheral arterial disease using assessment of neovascularization by 99mTc-tetrofosmin (TF) perfusion scintigraphy. Cell Transplant 13:429–437PubMedGoogle Scholar
  81. 81.
    Hasebe H, Osada M, Kodama Y, Fujioka D, Sano K, Nakamura T, Mitsumori T, Nakamura K, Kitta Y, Ichiki Y, Obata J, Kawabata K, Yanagi M, Sano S, Takano H, Umetani K, Kugiyama K (2004) [Therapeutic angiogenesis by autologous transplantation of bone-marrow cells in a patient with progressive limb ischemia due to arteriosclerosis obliterans: a case report]. J Cardiol 43:179–183PubMedGoogle Scholar
  82. 82.
    Nizankowski R, Petriczek T, Skotnicki A, Szczeklik A (2005) The treatment of advanced chronic lower limb ischaemia with marrow stem cell autotransplantation. Kardiol Pol 63:351–360 discussion 361PubMedGoogle Scholar
  83. 83.
    Gu Y, Zhang J, Qi L (2006) [A clinical study on implantation of autologous bone marrow mononuclear cells after bone marrow stimulation for treatment of lower limb ischemia]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 20:1017–1020PubMedGoogle Scholar
  84. 84.
    Bartsch T, Falke T, Brehm M, Zeus T, Kogler G, Wernet P, Strauer BE (2006) [Intra-arterial and intramuscular transplantation of adult, autologous bone marrow stem cells. Novel treatment for therapy-refractory peripheral arterial occlusive disease]. Dtsch Med Wochenschr 131:79–83PubMedGoogle Scholar
  85. 85.
    Gu Y, Zhang J, Qi L (2006) [Effective autologous bone marrow stem cell dosage for treatment of severe lower limb ischemia]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 20:504–506PubMedGoogle Scholar
  86. 86.
    Bartsch T, Falke T, Brehm M, Zeus T, Kogler G, Wernet P, Strauer BE (2006) [Transplantation of autologous adult bone marrow stem cells in patients with severe peripheral arterial occlusion disease]. Med Klin (Munich) 101(Suppl 1):195–197Google Scholar
  87. 87.
    Koshikawa M, Shimodaira S, Yoshioka T, Kasai H, Watanabe N, Wada Y, Seto T, Fukui D, Amano J, Ikeda U (2006) Therapeutic angiogenesis by bone marrow implantation for critical hand ischemia in patients with peripheral arterial disease: a pilot study. Curr Med Res Opin 22:793–798PubMedGoogle Scholar
  88. 88.
    Hernandez P, Cortina L, Artaza H, Pol N, Lam RM, Dorticos E, Macias C, Hernandez C, del Valle L, Blanco A, Martinez A, Diaz F (2007) 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 194:e52–56PubMedGoogle Scholar
  89. 89.
    Gu Y, Zhang J, Qi L (2007) [Comparative study on autologous implantation between bone marrow stem cells and peripheral blood stem cells for treatment of lower limb ischemia]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 21:675–678PubMedGoogle Scholar
  90. 90.
    Kajiguchi M, Kondo T, Izawa H, Kobayashi M, Yamamoto K, Shintani S, Numaguchi Y, Naoe T, Takamatsu J, Komori K, Murohara T (2007) Safety and efficacy of autologous progenitor cell transplantation for therapeutic angiogenesis in patients with critical limb ischemia. Circ J 71:196–201PubMedGoogle Scholar
  91. 91.
    Huang PP, Yang XF, Li SZ, Wen JC, Zhang Y, Han ZC (2007) 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 98:1335–1342PubMedGoogle Scholar
  92. 92.
    Saito Y, Sasaki K, Katsuda Y, Murohara T, Takeshita Y, Okazaki T, Arima K, Katsuki Y, Shintani S, Shimada T, Akashi H, Ikeda H, Imaizumi T (2007) Effect of autologous bone-marrow cell transplantation on ischemic ulcer in patients with Buerger's disease. Circ J 71:1187–1192PubMedGoogle Scholar
  93. 93.
    Van Tongeren RB, Hamming JF, Fibbe WE, Van Weel V, Frerichs SJ, Stiggelbout AM, Van Bockel JH, Lindeman JH (2008) Intramuscular or combined intramuscular/intra-arterial administration of bone marrow mononuclear cells: a clinical trial in patients with advanced limb ischemia. J Cardiovasc Surg (Torino) 49:51–58Google Scholar
  94. 94.
    Wester T, Jorgensen JJ, Stranden E, Sandbaek G, Tjonnfjord G, Bay D, Kolleros D, Kroese AJ, Brinchmann JE (2008) Treatment with autologous bone marrow mononuclear cells in patients with critical lower limb ischaemia. A pilot study. Scand J Surg 97:56–62PubMedGoogle Scholar
  95. 95.
    Huang PP, Li SZ, Han MZ, Xiao ZJ, Yang RC, Qiu LG, Han ZC (2004) Autologous transplantation of peripheral blood stem cells as an effective therapeutic approach for severe arteriosclerosis obliterans of lower extremities. Thromb Haemost 91:606–609PubMedGoogle Scholar
  96. 96.
    Lenk K, Adams V, Lurz P, Erbs S, Linke A, Gielen S, Schmidt A, Scheinert D, Biamino G, Emmrich F, Schuler G, Hambrecht R (2005) Therapeutical potential of blood-derived progenitor cells in patients with peripheral arterial occlusive disease and critical limb ischaemia. Eur Heart J 26:1903–1909PubMedGoogle Scholar
  97. 97.
    Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC (2005) Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care 28:2155–2160PubMedGoogle Scholar
  98. 98.
    Ishida A, Ohya Y, Sakuda H, Ohshiro K, Higashiuesato Y, Nakaema M, Matsubara S, Yakabi S, Kakihana A, Ueda M, Miyagi C, Yamane N, Koja K, Komori K, Takishita S (2005) Autologous peripheral blood mononuclear cell implantation for patients with peripheral arterial disease improves limb ischemia. Circ J 69:1260–1265PubMedGoogle Scholar
  99. 99.
    Yang XF, Wu YX, Wang HM, Xu YF, Lu X, Zhang YB, Wang F, Zhang Y (2005) [Autologous peripheral blood stem cells transplantation in treatment of 62 cases of lower extremity ischemic disorder.]. Zhonghua Nei Ke Za Zhi 44:95–98PubMedGoogle Scholar
  100. 100.
    Sugihara S, Yamamoto Y, Matsubara K, Ishida K, Matsuura T, Ando F, Igawa G, Narazaki G, Miake J, Tajima F, Nishio R, Nakayama B, Igawa O, Shigemasa C, Hisatome I (2006) Autoperipheral blood mononuclear cell transplantation improved giant ulcers due to chronic arteriosclerosis obliterans. Heart Vessels 21:258–262PubMedGoogle Scholar
  101. 101.
    Kawamura A, Horie T, Tsuda I, Ikeda A, Egawa H, Imamura E, Iida J, Sakata H, Tamaki T, Kukita K, Meguro J, Yonekawa M, Kasai M (2005) Prevention of limb amputation in patients with limbs ulcers by autologous peripheral blood mononuclear cell implantation. Ther Apher Dial 9:59–63PubMedGoogle Scholar
  102. 102.
    Kawamura A, Horie T, Tsuda I, Abe Y, Yamada M, Egawa H, Iida J, Sakata H, Onodera K, Tamaki T, Furui H, Kukita K, Meguro J, Yonekawa M, Tanaka S (2006) Clinical study of therapeutic angiogenesis by autologous peripheral blood stem cell (PBSC) transplantation in 92 patients with critically ischemic limbs. J Artif Organs 9:226–233PubMedGoogle Scholar
  103. 103.
    Zhang HK, Li M, Feng H (2007) [Autologous transplantation of peripheral blood stem cell in treatment of critical limb ischemia]. Zhejiang Da Xue Xue Bao Yi Xue Ban 36:360–363PubMedGoogle Scholar
  104. 104.
    Hoshino J, Ubara Y, Hara S, Sogawa Y, Suwabe T, Higa Y, Nakanishi S, Sawa N, Katori H, Takemoto F, Fujimoto Y, Ohta E, Ohara K, Takaichi K (2007) Quality of life improvement and long-term effects of peripheral blood mononuclear cell transplantation for severe arteriosclerosis obliterans in diabetic patients on dialysis. Circ J 71:1193–1198PubMedGoogle Scholar
  105. 105.
    Kudo FA, Nishibe T, Nishibe M, Yasuda K (2003) Autologous transplantation of peripheral blood endothelial progenitor cells (CD34+) for therapeutic angiogenesis in patients with critical limb ischemia. Int Angiol 22:344–348PubMedGoogle Scholar
  106. 106.
    Canizo MC, Lozano F, Gonzalez-Porras JR, Barros M, Lopez-Holgado N, Briz E, Sanchez-Guijo FM (2007) Peripheral endothelial progenitor cells (CD133+) for therapeutic vasculogenesis in a patient with critical limb ischemia. One year follow-up. . Cytotherapy 9:99–102PubMedGoogle Scholar
  107. 107.
    Kolvenbach R, Kreissig C, Ludwig E, Cagiannos C (2007) Stem cell use in critical limb ischemia. J Cardiovasc Surg (Torino) 48:39–44Google Scholar
  108. 108.
    Boda Z, Udvardy M, Farkas K, Toth J, Jambor L, Soltesz P, Razso K, Olah Z, Ilonczai P, Szarvas M, Litauszky K, Hunyadi J, Sipos T, Kappelmayer J, Vereb Z, Rajnavolgyi E (2008) [A pilot study with autologous bone marrow-derived stem cell therapy in patients with severe peripheral arterial disorder]. Orv Hetil 149:531–540PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Xabier L. Aranguren
    • 1
  • Catherine M. Verfaillie
    • 2
  • Aernout Luttun
    • 1
  1. 1.Center for Molecular and Vascular BiologyKatholieke Universiteit Leuven (KULeuven)LeuvenBelgium
  2. 2.Stamcel InstituutKULeuvenLeuvenBelgium

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