Download PDF
CC BY-NC-ND 4.0 · Indian J Radiol Imaging 2019; 29(04): 397-403
DOI: 10.4103/ijri.IJRI_385_19
Interventional Radiology

Stem cell therapy in critical limb ischemia: Current scenario and future trends

Arun Sharma
Department of Cardiovascular Radiology and Endovascular Interventions, All India Institute of Medical Sciences, New Delhi, India
,
Mumun Sinha
Department of Cardiovascular Radiology and Endovascular Interventions, All India Institute of Medical Sciences, New Delhi, India
,
Niraj Nirmal Pandey
Department of Radiodiagnosis, BRAIRCH, All India Institute of Medical Sciences, New Delhi, India
,
S H Chandrashekhara
Department of Cardiovascular Radiology and Endovascular Interventions, All India Institute of Medical Sciences, New Delhi, India
› Author Affiliations Financial support and sponsorship Nil.
› Further Information
   Permissions and Reprints

Abstract

Critical limb ischemia (CLI) represents the most severe manifestation of peripheral arterial disease (PAD). It imposes a huge economic burden and is associated with high short-term mortality and adverse cardiovascular outcomes. Prompt recognition and early revascularization, surgical or endovascular, with the aim of improving the inline bloodflow to the ischemic limb, are currently the standard of care. However, this strategy may not always be feasible or effective; hence, evaluation of newer pharmacological or angiogenic therapies for alleviating the symptoms of this alarming condition is of utmost importance. Cell-based therapies have shown promise in smaller studies; however, large-scale studies, demonstrating definite survival benefits, are entailed to ascertain their role in the management of CLI.

Keywords

Critical limb ischemia - peripheral arterial disease - stem cell therapy


Publication History

Received: 17 September 2019

Accepted: 18 November 2019

Article published online:
21 July 2021

© 2019. Indian Radiological Association. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Thieme Medical and Scientific Publishers Private Ltd.
A-12, Second Floor, Sector -2, NOIDA -201301, India

 

  • References

  • 1 Biancari F. Meta-analysis of the prevalence, incidence and natural history of critical limbischemia. J Cardiovasc Surg (Torino) 2013; 54: 663-9
    PubMedGoogle Scholar
  • 2 Nehler MR, Duval S, Diao L, Annex BH, Hiatt WR, Rogers K. et al. Epidemiology of peripheral arterial disease and critical limb ischemia in an insured national population. J Vasc Surg 2014; 60: 686-95
    CrossrefPubMedGoogle Scholar
  • 3 Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG. Intersociety consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 2007; 45 suppl S S5-67
    CrossrefPubMedGoogle Scholar
  • 4 Varu VN, Hogg ME, Kibbe MR. Critical limb ischemia. J Vasc Surg 2010; 51: 230-41
    CrossrefPubMedGoogle Scholar
  • 5 Bertele V, Roncaglioni MC, Pangrazzi J, Terzian E, Tognoni G. Clinical outcome and its predictors in 1560 patients with critical leg ischaemia. Eur J Vasc Endovasc Surg 1999; 18: 401-10
    CrossrefPubMedGoogle Scholar
  • 6 Wester T, Jørgensen JJ, Stranden E, Sandbaek G, Tjønnfjord G, Bay D. 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
  • 7 Chochola M, Pytlík R, Kobylka P, Skalická L, Kideryová L, Beran S. et al. Autologous intra-arterial infusion of bone marrow mononuclear cells in patients with critical leg ischemia. Int Angiol 2008; 27: 281-90
    Google Scholar
  • 8 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: 384-93
    CrossrefPubMedGoogle Scholar
  • 9 Tierney M, Garcia C, Bancone M, Sacco A, Personius KE. Innervation of dystrophic muscle after muscle stem cell therapy. Muscle Nerve 2016; 54: 763-8
    CrossrefPubMedGoogle Scholar
  • 10 Hao M, Wang R, Wang W. Cell therapies in cardiomyopathy: Current status of clinical trials. Anal Cell Pathol (Amst) 2017; 2017: 9404057
    PubMedGoogle Scholar
  • 11 Nagoshi N, Okano H. Applications of induced pluripotent stem cell technologies in spinal cord injury. J Neurochem 2017; 141: 848-60
    CrossrefPubMedGoogle Scholar
  • 12 Bierman HR. Bone marrow aspiration the posterior iliac crest, an additional safe site. Calif Med 1952; 77: 138-9
    PubMedGoogle Scholar
  • 13 Gu YQ, Zhang J, Guo LR, Qi LX, Zhang SW, Xu J. et al. Transplantation of autologous bone marrow mononuclear cells for patients with lower limb ischemia. Chin Med J (Engl) 2008; 121: 963-7
    CrossrefPubMedGoogle Scholar
  • 14 Gu Y, Zhang J, Qi L. 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 2006; 20: 1017-20
    PubMedGoogle Scholar
  • 15 Gu Y, Zhang J, Qi L. 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 2007; 21: 675-8
    PubMedGoogle Scholar
  • 16 Matoba S, Tatsumi T, Murohara T, Imaizumi T, Katsuda Y, Ito M. et al. Long-term clinical outcome after intramuscular implantation of bone marrow mononuclear cells (Therapeutic Angiogenesis by Cell Transplantation [TACT] trial) in patients with chronic limb ischemia. Am Heart J 2008; 156: 1010-8
    CrossrefPubMedGoogle Scholar
  • 17 Amann B, Luedemann C, Ratei R, Schmidt-Lucke JA. 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: 371-80
    CrossrefPubMedGoogle Scholar
  • 18 Amann B, Lüdemann C, Rückert R, Lawall H, Liesenfeld B, Schneider M. 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: 319-25
    CrossrefPubMedGoogle Scholar
  • 19 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 2012; 2: 1280-6
    CrossrefPubMedGoogle Scholar
  • 20 Iafrati MD, Hallett JW, Geils G, Pearl G, Lumsden A, Peden E. et al. Early results and lessons learned from a multicenter, randomized, double-blind trial of bone marrow aspirate concentrate in critical limb ischemia. J Vasc Surg 2011; 54: 1650-8
    CrossrefPubMedGoogle Scholar
  • 21 Walter DH, Krankenberg H, Balzer J, Kalka C, Baumgartner I, Schlüter 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: 26-37
    CrossrefPubMedGoogle Scholar
  • 22 Van Tongeren RB, Hamming JF, Fibbe WE, Van Weel V, Frerichs SJ, Stiggelbout AM. 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 (Torino) 2008; 40: 51-8
    Google Scholar
  • 23 Bartsch T, Brehm M, Zeus T, Kögler G, Wernet P, Strauer BE. Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (the TAM-PAD study). Clin Res Cardiol 2007; 96: 891-9
    CrossrefPubMedGoogle Scholar
  • 24 Ho TK, Shiwen X, Abraham D, Tsui J, Baker D. Stromal-cell-derived factor-1 (SDF-1)/CXCL12 as potential target of therapeutic angiogenesis in critical leg ischaemia. Cardiol Res Pract 2012; 2012: 143209
    PubMedGoogle Scholar
  • 25 Frangogiannis NG. Stromal cell-derived factor-1- mediated angiogenesis for peripheral arterial disease: Ready for prime time?. Circulation 2011; 123: 1267-9
    CrossrefPubMedGoogle Scholar
  • 26 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: 2155-60
    CrossrefPubMedGoogle Scholar
  • 27 Arai M, Misao Y, Nagai H, Kawasaki M, Nagashima K, Suzuki K. et al. Granulocyte colony-stimulating factor: A noninvasive regeneration therapy for treating atherosclerotic peripheral artery disease. Circ J 2006; 70: 1093-8
    CrossrefPubMedGoogle Scholar
  • 28 Barć P, Skóra J, Pupka A, Turkiewicz D, Dorobisz AT, Garcarek J. et al. Bone-marrow cells in therapy of critical limb ischemia of lower extremities-own experience. Acta Angiologica 2006; 12: 155-66
    Google Scholar
  • 29 Debin L, Youzhao J, Ziwen L, Xiaoyan L, Zhonghui Z, Bing C. Autologous transplantation of bone marrow mesenchymal stem cells on diabetic patients with lower limb ischemia. J Med Coll PLA 2008; 23: 106-15
    CrossrefGoogle Scholar
  • 30 Dash NR, Dash SN, Routray P, Mohapatra S, Mohapatra PC. Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res 2009; 12: 359-66
    CrossrefPubMedGoogle Scholar
  • 31 Procházka V, Gumulec J, Jalůvka F, Salounová D, Jonszta T, Czerný D. et al. Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer. Cell Transplant 2010; 19: 1413-24
    CrossrefPubMedGoogle Scholar
  • 32 Wen JC, Huang PP. Autologous peripheral blood mononuclear cells transplantation in treatment of 30 cases of critical limb ischemia: 3-year safety follow-up. J Clin Rehabil Tissue Eng Res 2010; 14: 8526-30
    Google Scholar
  • 33 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: 26-36
    CrossrefPubMedGoogle Scholar
  • 34 Jain P, Perakath B, Jesudason MR, Nayak S. The effect of autologous bone marrow-derived cells on healing chronic lower extremity wounds: Results of a randomized controlled study. Ostomy Wound Manage 2011; 57: 38-44
    PubMedGoogle Scholar
  • 35 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
    CrossrefPubMedGoogle Scholar
  • 36 Losordo DW, Kibbe MR, Mendelsohn F, Marston W, Driver VR, Sharafuddin M. et al. Autologous CD34+ Cell Therapy for Critical Limb Ischemia Investigators. A randomized, controlled pilot study of autologous CD34+cell therapy for critical limb ischemia. Circ Cardiovasc Interv 2012; 5: 821-30
    CrossrefPubMedGoogle Scholar
  • 37 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 Complications 2012; 26: 29-33
    CrossrefPubMedGoogle Scholar
  • 38 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
    CrossrefPubMedGoogle Scholar
  • 39 Li M, Zhou H, Jin X, Wang M, Zhang S, Xu L. Autologous bone marrow mononuclear cells transplant in patients with critical leg ischemia: Preliminary clinical results. Exp Clin Transplant 2013; 11: 435-9
    CrossrefPubMedGoogle Scholar
  • 40 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 2013; 121: 48-53
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Szabó GV, Kövesd Z, Cserepes J, Daróczy J, Belkin M, Acsády G. Peripheral blood-derived autologous stem cell therapy for the treatment of patients with late-stage peripheral artery disease-results of the short- and long-term follow-up. Cytotherapy 2013; 15: 1245-52
    CrossrefPubMedGoogle Scholar
  • 42 Raval AN, Schmuck EG, Tefera G, Leitzke C, Ark CV, Hei D. et al. Bilateral administration of autologous CD133+cells in ambulatory patients with refractory critical limb ischemia: Lessons learned from a pilot randomized, double-blind, placebo-controlled trial. Cytotherapy 2014; 16: 1720-32
    CrossrefPubMedGoogle Scholar
  • 43 Skóra J, Pupka A, Janczak D, Barć P, Dawiskiba T, Korta K. et al. Combined autologous bone marrow mononuclear cell and gene therapy as the last resort for patients with critical limb ischemia. Arch Med Sci 2015; 11: 325-31
    CrossrefPubMedGoogle Scholar
  • 44 Rigato M, Monami M, Fadini GP. Autologous cell therapy for peripheral arterial disease: Systematic review and meta-analysis of randomized, non-randomized, and non-controlled studies. Circ Res 2017; 120: 1326-40
    CrossrefPubMedGoogle Scholar
  • 45 Wahid FSA, Ismail NA, Wan Jamaludin WF, Muhamad NA, Mohamad Idris MA, Lai NM. Efficacy and safety of autologous cell-based therapy in patients with no-option critical limb ischaemia: A meta-analysis. Curr Stem Cell Res Ther 2018; 13: 265-83
    CrossrefPubMedGoogle Scholar
  • 46 Xie B, Luo H, Zhang Y, Wang Q, Zhou C, Xu D. Autologous stem cell therapy in critical limb ischemia: A meta-analysis of randomized controlled trials. Stem Cells Int 2018; 2018: 7528464
    PubMedGoogle Scholar
  • 47 Abdul Wahid SF, Ismail NA, Wan Jamaludin WF, Muhamad NA, Abdul Hamid MKA, Harunarashid H. et al. Autologous cells derived from different sources and administered using different regimens for ‘no-option’ critical lower limb ischaemia patients. Cochrane Database Syst Rev 2018; 8: CD010747
    PubMedGoogle Scholar
  • 48 Ohtake T, Mochida Y, Ishioka K, Oka M, Maesato K, Moriya H. et al. Autologous granulocyte colony-stimulating factor-mobilized peripheral blood CD34 positive cell transplantation for hemodialysis patients with critical limb ischemia: A prospective phase II clinical trial. Stem Cells Transl Med 2018; 7: 774-82
    CrossrefPubMedGoogle Scholar
  • 49 Liotta F, Annunziato F, Castellani S, Boddi M, Alterini B, Castellini G. et al. Therapeutic efficacy of autologous non-mobilized enriched circulating endothelial progenitors in patients with critical limb ischemia- The SCELTA trial. Circ J 2018; 82: 1688-98
    CrossrefPubMedGoogle Scholar
  • 50 Wang X, Zhang J, Cui W, Fang Y, Li L, Ji S. et al. Composite hydrogel modified by IGF-1C domain improves stem cell therapy for limb ischemia. ACS Appl Mater Interfaces 2018; 10: 4481-93
    CrossrefPubMedGoogle Scholar
  • 51 Qadura M, Terenzi DC, Verma S, Al-Omran M, Hess DA. Concise review: Cell therapy for critical limb ischemia: An integrated review of preclinical and clinical studies. Stem Cells 2018; 36: 161-71
    CrossrefPubMedGoogle Scholar
  • 52 Parikh PP, Liu ZJ, Velazquez OC. A molecular and clinical review of stem cell therapy in critical limb ischemia. Stem Cells Int 2017; 2017: 3750829
    CrossrefPubMedGoogle Scholar
  • 53 Karantalis V, Schulman IH, Balkan W, Hare JM. Allogeneic cell therapy: A new paradigm in therapeutics. Circ Res 2015; 116: 12-5
    CrossrefPubMedGoogle Scholar
  • 54 Berndt R, Hummitzsch L, Heß K, Albrecht M, Zitta K, Rusch R. et al. Allogeneic transplantation of programmable cells of monocytic origin (PCMO) improves angiogenesis and tissue recovery in critical limb ischemia (CLI): A translational approach. Stem Cell Res Ther 2018; 9: 117
    CrossrefPubMedGoogle Scholar