Autologous immuno magnetically selected CD133+ stem cells in the treatment of no-option critical limb ischemia: clinical and contrast enhanced ultrasound assessed results in eight patients

Vittorio Arici, Cesare Perotti, Calliada Fabrizio, Claudia Del Fante, Franco Ragni, Francesco Alessandrino, Gianluca Viarengo, Michele Pagani, Alessia Moia, Carmine Tinelli, Antonio Bozzani, Vittorio Arici, Cesare Perotti, Calliada Fabrizio, Claudia Del Fante, Franco Ragni, Francesco Alessandrino, Gianluca Viarengo, Michele Pagani, Alessia Moia, Carmine Tinelli, Antonio Bozzani

Abstract

Objectives: Demonstrate the safety and effectiveness of highly purified CD133+ autologous stem cells in critical limb ischemia (CLI).

Design: Prospective single-center not randomized. Clinicaltrials.gov identifier: NCT01595776 METHODS: Eight patients with a history of stable CLI were enrolled in a period of 2 years. After bone marrow stimulation and single leukapheresis collection, CD133+ immunomagnetic cell selection was performed. CD133+ cells in buffer phosphate suspension was administered intramuscularly. Muscular and arterial contrast enhanced ultra sound (CEUS), lesion evolution and pain management were assessed preoperatively and 3, 6 and 12 months after the implant.

Results: No patient had early or late complications related to the procedure. Two patients (25 %) didn't get any relief from the treatment and underwent major amputation. Six patients (75 %) had a complete healing of the wounds, rest pain cessation and walking recovery. An increase in CEUS values was shown in all eight patients at 6 months and in the six clinical healed patients at 12 months and had statistical relevance.

Conclusions: Highly purified autologous CD133+ cells can stimulate neo-angiogenesis, as based on clinical and CEUS data.

Figures

Fig. 1
Fig. 1
The diagrams show the percentage increase of both RBV and RBF both in muscle and in anterior tibial artery. RBF regional blood flow, RBV regional blood volume. In the x axis are months of follow-up. In the y-axis is the percentage of increase of the values of RBV and RBF compared to the baseline. Dotted lines represent single patient values. Continue line represents the mean percentage increase with the statistical significance. P values compare the value of mean increase to the baseline

References

    1. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, TASC II Working Group. 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, Clement D, Creager M, Jaff M, Mohler E, 3rd, Rutherford RB, Sheehan P, Sillesen H, Rosenfield K. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) Eur J Vasc Endovasc Surg. 2007;33(Suppl 1):S1–S75. doi: 10.1016/j.ejvs.2006.09.024.
    1. Döbert N, Britten M, Assmus B, Berner U, Menzel C, Lehmann R, Hamscho N, Schächinger V, Dimmeler S, Zeiher AM, Grünwald F. Transplantation of progenitor cells after reperfused acute myocardial infarction: evaluation of perfusion and myocardial viability with FDG-PET and thallium SPECT. Eur J Nucl Med Mol Imaging. 2004;31:1146–1151. doi: 10.1007/s00259-004-1490-4.
    1. Young PP, Vaughan DE, Hatzopoulos AK. Biological properties of endothelial progenitor cells and their potential for cell therapy. Prog Cardiovasc Dis. 2007;49:421–429. doi: 10.1016/j.pcad.2007.02.004.
    1. Losordo DW, Dimmeler S. Therapeutic angiogenesis and vasculogenesis for ischemic disease: part I: angiogenic cytokines. Circulation. 2004;109:2487–2491. doi: 10.1161/01.CIR.0000128595.79378.FA.
    1. Losordo DW, Dimmeler S. Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based therapies. Circulation. 2004;109:2692–2697. doi: 10.1161/01.CIR.0000128596.49339.05.
    1. Yamamoto K, Kondo T, Suzuki S, Izawa H, Kobayashi M, Emi N, Komori K, Naoe T, Takamatsu J, Murohara T. Molecular evaluation of endothelial progenitor cells in patients with ischemic limbs. Therapeutic effect by stem cell transplantation. Arterioscler Thromb Vasc Biol. 2004;24:e192–e196. doi: 10.1161/01.ATV.0000147730.78953.60.
    1. Arici V, Bozzani A, Ragni F, Perotti C, Del Fante C, Calliada F, Pagani M, Odero A. Autologous endothelial progenitor cells derived from peripheral blood for the treatment of critical limb ischemia in no-option patients: pilot study. Ital J Vas Endovasc Surg. 2010;17(Suppl 1):11–14.
    1. Duerschmied D, Olson L, Olschewski M, Rossknecht A, Freund G, Bode C, Hehrlein C. Contrast ultrasound perfusion imaging of lower extremities in peripheral arterial disease: a novel diagnostic method. Eur Heart J. 2006;27:310–315. doi: 10.1093/eurheartj/ehi636.
    1. Duerschmied D, Zhou Q, Rink E, Harder D, Freund G, Olschewski M, Bode C, Hehrlein C. Simplified contrast ultrasound accurately reveals muscle perfusion deficits and reflects collateralization in PAD. Atherosclerosis. 2009;202:505–512. doi: 10.1016/j.atherosclerosis.2008.05.046.
    1. Duerschmied D, Maletzki P, Freund G, Olschewski M, Seufert J, Bode C, Hehrlein C. Analysis of muscle microcirculation in advanced diabetes mellitus by contrast enhanced ultrasound. Diabetes Res Clin Pract. 2008;81:88–92. doi: 10.1016/j.diabres.2008.03.002.
    1. 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, Therapeutic Angiogenesis using Cell Transplantation (TACT) Study Investigators Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet. 2002;360:427–435. doi: 10.1016/S0140-6736(02)09670-8.
    1. Lawall H, Bramlage P, Amann B. Treatment of peripheral arterial disease using stem and progenitor cell therapy. J Vasc Surg. 2011;53:445–453. doi: 10.1016/j.jvs.2010.08.060.
    1. Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol. 2011;50:280–289. doi: 10.1016/j.yjmcc.2010.08.005.
    1. Cañizo MC, Lozano F, González-Porras JR, Barros M, López-Holgado N, Briz E, Sánchez-Guijo FM. Peripheral endothelial progenitor cells (CD133+) for therapeutic vasculogenesis in a patient with critical limb ischemia. One year follow-up. Cytotherapy. 2007;9:99–102. doi: 10.1080/14653240601034708.
    1. Kudo FA, Nishibe T, Nishibe M, Yasuda K. Autologous transplantation of peripheral blood endothelial progenitor cells (CD34+) for therapeutic angiogenesis in patients with critical limb ischemia. Int Angiol. 2003;22:344–348.
    1. Burt RK, Testori A, Oyama Y, Rodriguez HE, Yaung K, Villa M, Bucha JM, Milanetti F, Sheehan J, Rajamannan N, Pearce WH. Autologous peripheral blood CD133+ cell implantation for limb salvage in patients with critical limb ischemia. Bone Marrow Transplant. 2010;45(1):111–116. doi: 10.1038/bmt.2009.102.
    1. Cao P, Eckstein HH, De Rango P, Setacci C, Ricco JB, de Donato G, Becker F, Robert-Ebadi H, Diehm N, Schmidli J, Teraa M, Moll FL, Dick F, Davies AH, Lepäntalo M, Apelqvist J. Management of critical limb ischaemia and diabetic foot. Clinical practice guidelines of the European Society for vascular surgery. Chapter II: diagnostic methods. Eur J Vasc Endovasc Surg. 2011;42(Suppl 2):S13–S32. doi: 10.1016/S1078-5884(11)60010-5.
    1. Torsney E, Xu Q. Resident vascular progenitor cells. J Mol Cell Cardiol. 2011;50:304–311. doi: 10.1016/j.yjmcc.2010.09.006.
    1. Hazarika S, Dokun AO, Li Y, Popel AS, Kontos CD, Annex BH. Impaired angiogenesis after hindlimb ischemia in type 2 diabetes mellitus: differential regulation of vascular endothelial growth factor receptor 1 and soluble vascular endothelial growth factor receptor 1. Circ Res. 2007;101:948–956. doi: 10.1161/CIRCRESAHA.107.160630.
    1. Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. 2002;106:2781–2786. doi: 10.1161/01.CIR.0000039526.42991.93.

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