Abstract
Patients with advanced peripheral arterial disease may develop critical limb ischemia with rest pain, non-healing ulcerations, and eventually may require major amputation despite currently available revascularization technologies. Stem cell therapies hold promise as novel therapeutics to promote vasculogenesis and improve tissue perfusion in these patients. This article reviews the current state of stem cell therapy for patients with peripheral arterial disease, with a focus on the cell types that have been studied, barriers to clinical development, and development of new endpoints for clinical trials.
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Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007;45(Suppl S):S5–67.
Izquierdo-Porrera AM, Gardner AW, Bradham DD, Montgomery PS, Sorkin JD, Powell CC, et al. Relationship between objective measures of peripheral arterial disease severity to self-reported quality of life in older adults with intermittent claudication. J Vasc Surg. 2005;41(4):625–30.
O'Hare AM, Katz R, Shlipak MG, Cushman M, Newman AB. Mortality and cardiovascular risk across the ankle-arm index spectrum: results from the Cardiovascular Health Study. Circulation. 2006;113(3):388–93.
ACC/AHA. 2005 practice Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic). Circulation. 2006;113(11):1474–547.
Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA: J Am Med Assoc. 2001;286(11):1317–24.
Writing Group M, Writing Committee M, Accf/Aha Task Force M. 2011 ACCF/AHA Focused Update of the Guideline for the Management of patients with peripheral artery disease (Updating the 2005 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2011;124(18):2020–45.
European Stroke O, Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clement D, et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2011;32(22):2851–906.
Conte MS. Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) and the (hoped for) dawn of evidence-based treatment for advanced limb ischemia. J Vasc Surg. 2010;51(5 Suppl):69S–75.
Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. The Lancet. 2005;366(9501):1925-1934.
van Royen N, Piek JJ, Buschmann I, Hoefer I, Voskuil M, Schaper W. Stimulation of arteriogenesis; a new concept for the treatment of arterial occlusive disease. Cardiovasc Res. 2001;49(3):543–53.
Asahara T, Kawamoto A, Masuda H. Concise review: Circulating endothelial progenitor cells for vascular medicine. Stem Cells. 2011;29(11):1650–5.
Asahara T. Isolation of Putative Progenitor Endothelial Cells for Angiogenesis. Science. 1997;275(5302):964–6.
Cuende N, Rico L, Herrera C. Concise review: bone marrow mononuclear cells for the treatment of ischemic syndromes: medicinal product or cell transplantation? Stem Cells Transl Med. 2012;1(5):403–8.
Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, et al. Bone Marrow Origin of Endothelial Progenitor Cells Responsible for Postnatal Vasculogenesis in Physiological and Pathological Neovascularization. Circ Res. 1999;85(3):221–8.
Shintani S, Murohara T, Ikeda H, Ueno T, Sasaki K, Duan J, et al. Augmentation of Postnatal Neovascularization With Autologous Bone Marrow Transplantation. Circulation. 2001;103(6):897–903.
Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, 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(9331):427–35.
Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC. Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care. 2005;28(9):2155–60.
Ozturk A, Kucukardali Y, Tangi F, Erikci A, Uzun G, Bashekim C, et al. Therapeutical potential of autologous peripheral blood mononuclear cell transplantation in patients with type 2 diabetic critical limb ischemia. J Diabetes Complicat. 2012;26(1):29–33.
Pittenger MF. Multilineage Potential of Adult Human Mesenchymal Stem Cells. Science. 1999;284(5411):143–7.
Iwase T, Nagaya N, Fujii T, Itoh T, Murakami S, Matsumoto 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(3):543–51.
Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy. 2005;7(5):393–5.
•• Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract. 2011;92(1):26–36. This randomized, controlled trial in diabetics with critical limb ischemia demonstrated improvements in ABIs, TcO2, and pain free walking time associated with both BM-MNCs and BM-MSCs. BM-MSCs showed faster ulcer healing compared to BM-MNC.
Yan J, Tie G, Xu TY, Cecchini K, Messina LM. Mesenchymal Stem Cells as a Treatment for Peripheral Arterial Disease: Current Status and Potential Impact of Type II Diabetes on Their Therapeutic Efficacy. Stem Cell Rev. 2013;9(3):360–72.
Bartel RL, Booth E, Cramer C, Ledford K, Watling S, Zeigler F. From Bench to Bedside: Review of Gene and Cell-Based Therapies and the Slow Advancement into Phase 3 Clinical Trials, with a Focus on Aastrom's Ixmyelocel-T. Stem Cell Rev. 2013;9(3):373–83.
Powell RJ, Comerota AJ, Berceli SA, Guzman R, Henry TD, Tzeng E, et al. Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia. J Vasc Surg. 2011;54(4):1032–41.
Powell RJ, Marston WA, Berceli SA, Guzman R, Henry TD, Longcore AT, et al. Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: the randomized, double-blind, placebo-controlled RESTORE-CLI trial. Mol Ther: J Am Soc Gene Ther. 2012;20(6):1280–6.
Kirana S, Stratmann B, Prante C, Prohaska W, Koerperich H, Lammers D, et al. Autologous stem cell therapy in the treatment of limb ischaemia induced chronic tissue ulcers of diabetic foot patients. Int J Clin Pract. 2012;66(4):384–93.
Hess DA, Meyerrose TE, Wirthlin L, Craft TP, Herrbrich PE, Creer MH, et al. Functional characterization of highly purified human hematopoietic repopulating cells isolated according to aldehyde dehydrogenase activity. Blood. 2004;104(6):1648–55.
Hess DA, Wirthlin L, Craft TP, Herrbrich PE, Hohm SA, Lahey R, et al. Selection based on CD133 and high aldehyde dehydrogenase activity isolates long-term reconstituting human hematopoietic stem cells. Blood. 2006;107(5):2162–9.
Capoccia BJ, Robson DL, Levac KD, Maxwell DJ, Hohm SA, Neelamkavil MJ, et al. Revascularization of ischemic limbs after transplantation of human bone marrow cells with high aldehyde dehydrogenase activity. Blood. 2009;113(21):5340–51.
Perin EC, Silva G, Gahremanpour A, Canales J, Zheng Y, Cabreira-Hansen MG, et al. A randomized, controlled study of autologous therapy with bone marrow-derived aldehyde dehydrogenase bright cells in patients with critical limb ischemia. Catheter Cardiovasc Interv: Off J Soc Cardiac Angiography Interv. 2011;78(7):1060–7.
•• Losordo DW, Kibbe MR, Mendelsohn F, Marston W, Driver VR, Sharafuddin M, et al. A randomized, controlled pilot study of autologous CD34+ cell therapy for critical limb ischemia. Circ Cardiovasc Interv. 2012;5(6):821–30. This randomized, controlled trial showed that G-CSF mobilized, CD34+ peripheral blood is associated with a dose related trend toward reduced amputations in patients with critical limb ischemia.
Szoke K, Brinchmann JE. Concise review: therapeutic potential of adipose tissue-derived angiogenic cells. Stem Cells Transl Med. 2012;1(9):658–67.
Miranville A, Heeschen C, Sengenes C, Curat CA, Busse R, Bouloumie A. Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation. 2004;110(3):349–55.
Murohara T. Autologous adipose tissue as a new source of progenitor cells for therapeutic angiogenesis. J Cardiol. 2009;53(2):155–63.
Kondo K, Shintani S, Shibata R, Murakami H, Murakami R, Imaizumi M, et al. Implantation of adipose-derived regenerative cells enhances ischemia-induced angiogenesis. Arterioscler Thromb Vasc Biol. 2009;29(1):61–6.
Marino G, Moraci M, Armenia E, Orabona C, Sergio R, De Sena G, et al. Therapy with autologous adipose-derived regenerative cells for the care of chronic ulcer of lower limbs in patients with peripheral arterial disease. J Surg Res. 2013.
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.
Taura D, Sone M, Homma K, Oyamada N, Takahashi K, Tamura N, et al. Induction and isolation of vascular cells from human induced pluripotent stem cells–brief report. Arterioscler Thromb Vasc Biol. 2009;29(7):1100–3.
• Rufaihah AJ, Huang NF, Jame S, Lee JC, Nguyen HN, Byers B, et al. Endothelial cells derived from human iPSCS increase capillary density and improve perfusion in a mouse model of peripheral arterial disease. Arterioscler Thromb Vasc Biol. 2011;31(11):e72–9. This group demonstrated that human induced pluripotent stem cells can differentiate into human endothelial cells in vitro, and improve perfusion in mice with hind limb ischemia.
• Lian Q, Zhang Y, Zhang J, Zhang HK, Wu X, Zhang Y, et al. Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemia in mice. Circulation. 2010;121(9):1113–23. This group successfully transformed human induced pluripotent stem cells into to MSCs which when administered to mice with hind limb ischemia resulted in improved perfusion and blood vessel formation, greater than that associated BM-MSC.
Gupta PK, Chullikana A, Parakh R, Desai S, Das A, Gottipamula S, et al. A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia. J Transl Med. 2013;11:143.
Cho SW, Moon SH, Lee SH, Kang SW, Kim J, Lim JM, et al. Improvement of postnatal neovascularization by human embryonic stem cell derived endothelial-like cell transplantation in a mouse model of hindlimb ischemia. Circulation. 2007;116(21):2409–19.
Murohara T, Ikeda H, Duan J, Shintani S, Sasaki K, Eguchi H, et al. Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest. 2000;105(11):1527–36.
Wong WT, Huang NF, Botham CM, Sayed N, Cooke JP. Endothelial cells derived from nuclear reprogramming. Circ Res. 2012;111(10):1363–75.
Raval Z, Losordo DW. Cell therapy of peripheral arterial disease: from experimental findings to clinical trials. Circ Res. 2013;112(9):1288–302.
• Walter DH, Krankenberg H, Balzer JO, Kalka C, Baumgartner I, Schluter M, et al. Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized-start, placebo-controlled pilot trial (PROVASA). Circ Cardiovasc Interv. 2011;4(1):26–37. This randomized, controlled trial showed that BM-MNC can be safely administered by intra-arterial injection in patient with critical limb ischemia. Treatment was associated with significant improvements in ulcer size and pain score compared to placebo.
Kinlay S. Outcomes for clinical studies assessing drug and revascularization therapies for claudication and critical limb ischemia in peripheral artery disease. Circulation. 2013;127(11):1241–50.
Wright KL, Seiberlich N, Jesberger JA, Nakamoto DA, Muzic RF, Jr., Griswold MA. Simultaneous magnetic resonance angiography and perfusion (MRAP) measurement: Initial application in lower extremity skeletal muscle. J Magn Reson Imaging: JMRI. 2013.
Subhash HM, Leahy MJ. Microcirculation imaging based on full-range high-speed spectral domain correlation mapping optical coherence tomography. J Biomed Opt. 2014;19(2):21103.
Srinivasan VJ, Jiang JY, Yaseen MA, Radhakrishnan H, Wu W, Barry S, et al. Rapid volumetric angiography of cortical microvasculature with optical coherence tomography. Opt Lett. 2010;35(1):43–5.
Benoit E, O’Donnell Jr TF, Iafrati MD, Asher E, Bandyk DF, Hallett JW, et al. The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design. J Transl Med. 2011;9:165.
Mohammadzadeh L, Samedanifard SH, Keshavarzi A, Alimoghaddam K, Larijani B, Ghavamzadeh A, et al. Therapeutic outcomes of transplanting autologous granulocyte colony-stimulating factor-mobilised peripheral mononuclear cells in diabetic patients with critical limb ischaemia. Exp Clin Endocrinol Diabetes: Off J Ger Soc Endocrinol Ger Diabetes Assoc. 2013;121(1):48–53.
Prochazka V, Gumulec J, Jaluvka F, Salounova D, Jonszta T, Czerny D, et al. Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer. Cell Transplant. 2010;19(11):1413–24.
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Nitin K. Gupta, Ehrin J. Armstrong, and Sahil A. Parikh declare that they have no conflict of interest.
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Gupta, N.K., Armstrong, E.J. & Parikh, S.A. The Current State of Stem Cell Therapy for Peripheral Artery Disease. Curr Cardiol Rep 16, 447 (2014). https://doi.org/10.1007/s11886-013-0447-2
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DOI: https://doi.org/10.1007/s11886-013-0447-2