Mesenchymal stromal cells for the treatment of critical limb ischemia: context and perspective

Hendrik Gremmels, Joost O Fledderus, Martin Teraa, Marianne C Verhaar, Hendrik Gremmels, Joost O Fledderus, Martin Teraa, Marianne C Verhaar

Abstract

Cell therapy using mesenchymal stromal cells (MSCs) is a promising new avenue of treatment for critical limb ischemia (CLI). Preclinical studies have suggested that MSCs enhance neovascularization in ischemic limbs. In this commentary, we discuss a recent study by Gupta and colleagues, one of the first human trials using allogeneic MSCs for CLI, in relation to the current state of knowledge regarding cell therapy for CLI.

Figures

Figure 1
Figure 1
Improvements in ankle-brachial index (ABI) after cell therapy. Meta-analytic scatterplot with meta-regression lines shows improvements in ABI compared with baseline after injection of a cell-therapy product or placebo. The two bone marrow mononuclear cell (BMC) cohorts in the study by Tateishi-Yuyama and colleagues [9] were included separately. Regression lines were fit with a mixed model using REML (restricted maximum likelihood) estimation; bands show 95% confidence intervals. This figure was prepared with the ‘metafor’ [11] package in ‘R’. MSC, mesenchymal stromal cell.

References

    1. Gupta PK, Chullikana A, Parakh R, Desai S, Das A, Gottipamula S, Krishnamurthy S, Anthony N, Pherwani A, Majumdar AS. 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;4:143. doi: 10.1186/1479-5876-11-143.
    1. Teraa M, Sprengers RW, van der Graaf Y, Peters CEJ, Moll FL, Verhaar MC. Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized controlled clinical trials. Ann Surg. 2013. [Epub ahead of print]
    1. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003;4:890–896. doi: 10.1016/S0301-472X(03)00110-3.
    1. Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ. Safety of Cell Therapy with Mesenchymal Stromal Cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS ONE. 2012;4:e47559. doi: 10.1371/journal.pone.0047559.
    1. Huang X-P, Sun Z, Miyagi Y, McDonald Kinkaid H, Zhang L, Weisel RD, Li RK. Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair. Circulation. 2010;4:2419–2429. doi: 10.1161/CIRCULATIONAHA.110.955971.
    1. Schwarz TM, Leicht SF, Radic T, Rodriguez-Araboalaza I, Hermann PC, Berger F, Saif J, Böcker W, Ellwart JW, Aicher A, Heeschen C. Vascular incorporation of endothelial colony-forming cells is essential for functional recovery of murine ischemic tissue following cell therapy. Arterioscler Thromb Vasc Biol. 2012;4:e13–e21. doi: 10.1161/ATVBAHA.111.239822.
    1. Iwase T, Nagaya N, Fujii T, Itoh T, Murakami S, Matsumoto T, Kangawa K, Kitamura S. Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia. Cardiovasc Res. 2005;4:543–551. doi: 10.1016/j.cardiores.2005.02.006.
    1. Lu D, Chen B, Liang Z, Deng W, Jiang Y, Li S, Xu J, Wu Q, Zhang Z, Xie B, Chen S. 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;4:26–36. doi: 10.1016/j.diabres.2010.12.010.
    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;4:427–435. doi: 10.1016/S0140-6736(02)09670-8.
    1. Walter DH, Krankenberg H, Balzer JO, Kalka C, Baumgartner I, Schlüter M, Tonn T, Seeger F, Dimmeler S, Lindhoff-Last E, Zeiher AM. PROVASA Investigators. 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. doi: 10.1161/CIRCINTERVENTIONS.110.958348.
    1. Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Software. 2010;4:1–48.
    1. Jeong H, Yim HW, Cho Y, Park HJ, Jeong S, Kim H-B, Hong W, Kim H. The effect of rigorous study design in the research of autologous bone marrow-derived mononuclear cell transfer in patients with acute myocardial infarction. Stem Cell Res Ther. 2013;4:82. doi: 10.1186/scrt233.
    1. Idei N, Soga J, Hata T, Fujii Y, Fujimura N, Mikami S, Maruhashi T, Nishioka K, Hidaka T, Kihara Y, Chowdhury M, Noma K, Taguchi A, Chayama K, Sueda T, Higashi Y. Cell therapy for critical limb ischemia: moving forward one step at a time. Circ Cardiovasc Interv. 2011;4:2–5. doi: 10.1161/CIRCINTERVENTIONS.110.960716.
    1. Ryu JC, Davidson BP, Xie A, Qi Y, Zha D, Belcik JT, Caplan ES, Woda JM, Hedrick CC, Hanna RN, Lehman N, Zhao Y, Ting A, Lindner JR. Molecular imaging of the paracrine proangiogenic effects of progenitor cell therapy in limb ischemia. Circulation. 2013;4:710–719. doi: 10.1161/CIRCULATIONAHA.112.116103.
    1. Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE. 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;4:678–685. doi: 10.1161/.
    1. Liew A, O'Brien T. Therapeutic potential for mesenchymal stem cell transplantation in critical limb ischemia. Stem Cell Res Ther. 2012;4:28. doi: 10.1186/scrt119.
    1. Bianco P, Cao X, Frenette PS, Mao JJ, Robey PG, Simmons PJ, Wang C-Y. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med. 2013;4:35–42. doi: 10.1038/nm.3028.

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