Surgical and cell therapy in critical limb ischemia: Current evidence and rationale for combined treatment with special focus on diabetic patients

Ottorino Del Foco; Antonio Bencomo-Hernandez; Yandy Castillo-Aleman; Pierdanilo Sanna; Stefano Benedetti; Enrico Dassen

doi:10.4103/jdep.jdep_52_21

Journal of Diabetes and Endocrine Practice, Inhaltsverzeichnis

CC BY-NC-ND 4.0 · Journal of Diabetes and Endocrine Practice 2021; 04(04): 154-159
DOI: 10.4103/jdep.jdep_52_21

Review Article

Surgical and cell therapy in critical limb ischemia: Current evidence and rationale for combined treatment with special focus on diabetic patients

Ottorino Del Foco

¹Abu Dhabi Stem Cells Center, United Arab Emirates

²Yas Clinic Khalifa City, Abu Dhabi, United Arab Emirates

,

Antonio Bencomo-Hernandez

¹Abu Dhabi Stem Cells Center, United Arab Emirates

,

Yandy Castillo-Aleman

¹Abu Dhabi Stem Cells Center, United Arab Emirates

,

Pierdanilo Sanna

¹Abu Dhabi Stem Cells Center, United Arab Emirates

²Yas Clinic Khalifa City, Abu Dhabi, United Arab Emirates

,

Stefano Benedetti

¹Abu Dhabi Stem Cells Center, United Arab Emirates

²Yas Clinic Khalifa City, Abu Dhabi, United Arab Emirates

,

Enrico Dassen

¹Abu Dhabi Stem Cells Center, United Arab Emirates

²Yas Clinic Khalifa City, Abu Dhabi, United Arab Emirates

› Institutsangaben

Abstract

Critical limb ischemia (CLI) is considered the end-stage of peripheral arterial disease, with a prevalence between 2% and 4% in the general population and more than 15% in older adults. One-year major amputation rate can reach 30%, and diabetic patients are five times more likely to develop CLI than nondiabetics. The vascular damage and the complexity in the anatomical extension of the lesions are also worse in people with diabetes with poorer outcomes after vascularization attempts. Following the classifications suggested by international guidelines, we can define the presence of CLI and have a precise evaluation of the amputation risk and the best revascularization procedure for the patient. Nowadays, new endovascular techniques and devices make it possible to treat tibial vessels and even arteries below the ankle with promising initial results. Nevertheless, the re-occlusions rate and the need to re-do treatments at 1 year remain between 30% and 50%. The disease progression and hyperplasia can because it. However, the damage at the microcirculatory level can also lead to a decrease in tissue runoff and an increase in peripheral resistance, which determine the revascularization failure. In the last 20 years, several trials have been designed to avoid amputation in patients with no surgical options. The aim is to find a valid cellular base therapy to create a new vessel web in the ischemic tissue based on the angiogenetic power that stem cells have already demonstrated in vitro and animal studies. Different types of cells have been tested with different concentrations and administration routes with promising results. CD34⁺ Mononuclear cells, Mesenchymal stem cells, growth factors have demonstrated their contribution to the neo-angiogenesis in ischemic areas. At Abu Dhabi Stem Cells Center, we created a cellular cocktail as an adjunct treatment to surgical revascularization. We think that acting at the microcirculatory and immunological level. We may reduce postsurgery hyperplasia and increase tissue perfusion, ultimately prolonging the patency of revascularization procedures.

Keywords

Critical limb ischemia - endovascular - major amputation - mesenchymal stem cells - peripheral arterial disease - surgical revascularization

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References
1 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.
2 Reinecke H, Malyar M. Chapter 68: Epidemiology and global burden of peripheral arterial disease and aortic aneurysms. In: John Camm A, Lüscher TF, Maurer G, Serruys PW, editors. ESC Cardiovascular Medicine. 3rd ed. OxFord: Oxford University Press; 2019. [doi: 10.1093/med/9780198784906.003.0068_update_001]. Available from: https://oxfordmedicine.com/view/100.1093/med/9780198784906.001.0001/med-9780198784906-chapter-68. [Last accessed on 2021 Nov 21].
3 Diehm N, Shang A, Silvestro A, Do DD, Dick F, Schmidli J, et al. Association of cardiovascular risk factors with pattern of lower limb atherosclerosis in 2659 patients undergoing angioplasty. Eur J Vasc Endovasc Surg 2006;31:59-63.
4 International Diabetes Federation. IDF Diabetes Atlas. 10th ed. Brussels, Belgium: 2021. Available from: https://diabetesatlas.org/data/en/country/208/ae.html. [Last accessed on 2021 Nov 21].
5 Conte MS, Bradbury AW, Kolh P, White JV, Dick F, Fitridge R, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg 2019;58 Suppl 1:S1-09.e33.
6 Isner JM, Pieczek A, Schainfeld R, Blair R, Haley L, Asahara T, et al. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet 1996;348:370-4.
7 Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M, et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A 2000;97:3422-7.
8 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;360:427-35.
9 Shigematsu H, Yasuda K, Iwai T, Sasajima T, Ishimaru S, Ohashi Y, et al. Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia. Gene Ther 2010;17:1152-61.
10 Masaki I, Yonemitsu Y, Yamashita A, Sata S, Tanii M, Komori K, et al. Angiogenic gene therapy for experimental critical limb ischemia: Acceleration of limb loss by overexpression of vascular endothelial growth factor 165 but not of fibroblast growth factor-2. Circ Res 2002;90:966-73.
11 Nakamura-Ishizu A, Takizawa H, Suda T. The analysis, roles and regulation of quiescence in hematopoietic stem cells. Development 2014;141:4656-66.
12 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;66:543-51.
13 Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, 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. Circ Res 2004;94:678-85.
14 Hare JM, DiFede DL, Rieger AC, Florea V, Landin AM, El-Khorazaty J, et al. Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: POSEIDON-DCM trial. J Am Coll Cardiol 2017;69:526-37.
15 Abou-El-Enein M, Bauer G, Medcalf N, Volk HD, Reinke P. Putting a price tag on novel autologous cellular therapies. Cytotherapy 2016;18:1056-61.
16 Siracuse JJ, Menard MT, Eslami MH, Kalish JA, Robinson WP, Eberhardt RT, et al. Comparison of open and endovascular treatment of patients with critical limb ischemia in the Vascular Quality Initiative. J Vasc Surg 2016;63:958-65.e1.
17 Horie T, Yamazaki S, Hanada S, Kobayashi S, Tsukamoto T, Haruna T, et al. Outcome from a randomized controlled clinical trial- improvement of peripheral arterial disease by granulocyte colony-stimulating factor-mobilized autologous peripheral-blood-mononuclear cell transplantation (IMPACT). Circ J 2018;82:2165-74.
18 Pignon B, Sevestre MA, Kanagaratnam L, Pernod G, Stephan D, Emmerich J, et al. Autologous bone marrow mononuclear cell implantation and its impact on the outcome of patients with critical limb ischemia- results of a randomized, double-blind, placebo-controlled trial. Circ J 2017;81:1713-20.
19 Teraa M, Sprengers RW, Schutgens RE, Slaper-Cortenbach IC, van der Graaf Y, Algra A, et al. Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: The randomized, double-blind, placebo-controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial. Circulation 2015;131:851-60.
20 Dong Z, Chen B, Fu W, Wang Y, Guo D, Wei Z, et al. Transplantation of purified CD34+cells in the treatment of critical limb ischemia. J Vasc Surg 2013;58:404-11.e3.
21 Dubsky M, Jirkovska A, Bem R, Fejfarova V, Pagacova L, Sixta B, et al. Both autologous bone marrow mononuclear cell and peripheral blood progenitor cell therapies similarly improve ischaemia in patients with diabetic foot in comparison with control treatment. Diabetes Metab Res Rev 2013;29:369-76.
22 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;5:821-30.
23 Walter DH, Krankenberg H, Balzer JO, 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.
24 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.
25 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.
26 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.
27 Pan T, Wei Z, Fang Y, Dong Z, Fu W. Therapeutic efficacy of CD34+cell-involved mononuclear cell therapy for no-option critical limb ischemia: A meta-analysis of randomized controlled clinical trials. Vasc Med 2018;23:219-31.
28 Rigato M, Monami M, Fadini GP. Autologous cell therapy for peripheral arterial disease: Systematic review and meta-analysis of randomized, nonrandomized, and noncontrolled studies. Circ Res 2017;120:1326-40.
29 Iwasaki H, Kawamoto A, Ishikawa M, Oyamada A, Nakamori S, Nishimura H, et al. Dose-dependent contribution of CD34-positive cell transplantation to concurrent vasculogenesis and cardiomyogenesis for functional regenerative recovery after myocardial infarction. Circulation 2006;113:1311-25.
30 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.
31 Howell C, Douglas K, Cho G, El-Ghariani K, Taylor P, Potok D, et al. Guideline on the clinical use of apheresis procedures for the treatment of patients and collection of cellular therapy products. British Committee for Standards in Haematology. Transfus Med 2015;25:57-78.
32 Basile DP, Yoder MC. Circulating and tissue-resident endothelial progenitor cells. J Cell Physiol 2014;229:10-6.
33 Pavlović M., Radotić K. Stemness and stem cell markers. In: Animal and Plant Stem Cells. Cham: Springer; 2017. [doi: 10.1007/978-3-319-47763-3_5].
34 Le Blanc K, Ringdén O. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005;11:321-34.
35 Hassan M, Yazid MD, Yunus MH, Chowdhury SR, Lokanathan Y, Idrus RB, et al. Large-Scale expansion of human mesenchymal stem cells. Stem Cells Int 2020;9529465.
36 Nekanti U, Mohanty L, Venugopal P, Balasubramanian S, Totey S, Ta M. Optimization and scale-up of Wharton's jelly-derived mesenchymal stem cells for clinical applications. Stem Cell Res 2010;5:244-54.
37 Renesme L, Cobey KD, Le M, Lalu MM, Thebaud B. Establishment of a consensus definition for mesenchymal stromal cells (MSC) and reporting guidelines for clinical trials of MSC therapy: A modified Delphi study protocol. BMJ Open 2021;11:e054740.
38 Attanasio S, Snell J. Therapeutic angiogenesis in the management of critical limb ischemia: Current concepts and review. Cardiol Rev 2009;17:115-20.
39 Qian Y, Han Q, Chen W, Song J, Zhao X, Ouyang Y, et al. Platelet-rich plasma derived growth factors contribute to stem cell differentiation in musculoskeletal regeneration. Front Chem 2017;5:89.
40 Brokhman I, Bacher J, Galea A. A novel method for the preparation and prolonged storage of growth factors and cytokines obtained from platelet rich plasma. Osteoarthritis Cartilage 2020;28:S526-7.