Efficacy and Safety of Mesenchymal Stem Cell Therapy in Chronic Limb-Threatening Ischemia: A Meta-analysis of Randomized Controlled Trials
Keywords:
Chronic Limb-Threatening Ischemia, Mesenchymal Stem Cell, Meta-analysis, Safety, Efficacy
Abstract
Background: Chronic Limb-Threatening Ischemia (CLTI) represents the terminal stage of peripheral artery disease, carrying substantial morbidity and mortality. Despite various therapeutic strategies, clinical outcomes remain unsatisfactory, highlighting the urgent need for novel treatments. While Mesenchymal Stem Cells (MSCs) show promise at the cellular level, human studies are limited, preventing generalizable conclusions at this time. This study aimed to systematically assess the efficacy and safety of MSCs implantation in CLTI.
Methods: PRISMA 2020-guided meta-analysis of intervention. Various databases were searched using keywords based of the PICOS framework. The PICOS framework guided our approach: Patients (CLTI), Intervention (MSCs), Comparison (Placebo OR Control), Outcome (Amputation, Ulcer Healing Rate, Rest Pain Change, Ankle-Brachial Index, Adverse Effect), and Study (Randomized Controlled Trial [RCT]). Statistical analysis was performed using Review Manager (RevMan 5.4.1) and RStudio (R.4.4.3). An Independent Risk-of-Bias 2 (RoB2) risk of bias assessment was performed.
Results: Seven RCTs were included with a total of 270 patients. Meta-analysis showed that MSCs were more effective than the control group on suppressing the amputation rate (Odds Ratio [OR] = 0.40, 95% Confidence Interval [CI] = 0.17–0.95, p = 0.04). Ulcer healing rate was significantly higher in the MSCs therapy group compared to the control group (OR = 9.79, 95% CI = 2.59–36.98, p = 0.0008). Moreover, MSCs therapy markedly improved clinical outcomes, including rest pain score (Mean Difference [MD] = –1.88, 95% CI = –2.93 to –0.84, p = 0.0004) and ankle-brachial index (MD = 0.16, 95% CI = 0.09–0.22, p < 0.00001). Interestingly, MSCs therapy showed an excellent safety profile, with negligible gastrointestinal-hepatobiliary events and only 4% mild infections or musculoskeletal effects.
Conclusion: This review shows that MSCs therapy offers a transformative approach for CLTI, significantly improving limb outcomes and perfusion while maintaining an excellent safety profile.
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References
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23. Gao W, Chen D, Liu G, Ran X. Autologous stem cell therapy for peripheral arterial disease : a systematic review and meta-analysis of randomized controlled trials. 2019;1–14.
24. Xie B, Luo H, Zhang Y, Wang Q, Zhou C, Xu D. Review Article Autologous Stem Cell Therapy in Critical Limb Ischemia : A Meta-Analysis of Randomized Controlled Trials. 2018;2018.
25. Kareti YB, Kumar V, Desai SC, Ramswamy CA, Gowda SS. Stem Cell Therapy in No Option Chronic Limb-threatening Ischemia. Indian J Vasc Endovasc Surg [Internet]. 2025;12(2). Available from: https://journals.lww.com/ijvs/fulltext/2025/04000/stem_cell_therapy_in_no_option_chronic.7.aspx
26. Huerta CT, Voza FA, Ortiz YY, Liu ZJ, Velazquez OC. Mesenchymal stem cell-based therapy for non-healing wounds due to chronic limb-threatening ischemia: A review of preclinical and clinical studies. Front Cardiovasc Med. 2023;10:1113982.
27. 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. 2013;48–53.
28. Navarro LVL, Chen X, Tatiana, Lady, Viviescas G, Roa AKA, Gonzalez MLL, et al. Mesenchymal stem cells for critical limb ischemia : their function , mechanism , and therapeutic potential. 2022;1–17.
29. Bagno LL, Salerno AG, Balkan W, Hare JM. Mechanism of action of mesenchymal stem cells (MSCs): Impact of Delivery Method. 2023;22(4):449–63.
30. Tebebi PA, Kim SJ, Williams RA, Milo B, Frenkel V, Burks SR, et al. Improving the therapeutic efficacy of mesenchymal stromal cells to restore perfusion in critical limb ischemia through pulsed focused ultrasound. Nat Publ Gr. 2017;(September 2016):1–11.
2. Hata Y, Iida O, Nakao S, Toyoshima T, Yasunaga M, Nohara H, et al. Trends in Characteristics and Treatment of Patients With Chronic Limb-Threatening Ischemia Undergoing Endovascular Therapy. 2025;5(10).
3. Desai S, Sharma D, Srinivas R, Balaji V, Thakore V, Bedi VS, et al. Mesenchymal stromal cell therapy ( REGENACIP ® ), a promising treatment option in chronic limb threatening ischemia – a narrative review. 2024;
4. Kwong M, Rajasekar G, Utter GH, Nuño M. Updated estimates for the burden of chronic limb-threatening ischemia in the Medicare population. J Vasc Surg [Internet]. 2023;77(6):1760–75. Available from: https://doi.org/10.1016/j.jvs.2023.01.200
5. Effendi H, Suhartono R, Kekalih A. Evaluation of the Influence of Risk Factors on the Time of Onset of Ulcers , Rest Pain and New Gangrene After Angioplasty in Chronic Limb Threatening Ischemia ( CLTI ) Patients at Dr . Cipto Mangunkusumo Hospital. 2021;969–87.
6. Ventoruzzo G, Mazzitelli G, Ruzzi U, Liistro F, Scatena A, Martelli E. Limb Salvage and Survival in Chronic Limb-Threatening Ischemia : The Need for a Fast-Track Team-Based Approach. 2023;(Cli).
7. Hon K, Bain M, Minns G, Colley E, Fitridge R. Conservative management of patients with end-stage chronic limb-threatening ischaemia in the community. Aust J Gen Pract [Internet]. 2024 Oct 30;53:53–62. Available from: https://www1.racgp.org.au/ajgp/2024/supplement-november/conservative-management-of-patients
8. Aihara H, Soga Y, Mii S, Okazaki J, Yamaoka T, Kamoi D, et al. Comparison of long-term outcome after endovascular therapy versus bypass surgery in claudication patients with Trans-Atlantic Inter-Society Consensus-II C and D femoropopliteal disease. Circ J. 2014;78(2):457–64.
9. Singh GD, Brinza EK, Hildebrand J, Waldo SW, Foley TR, Laird JR, et al. Midterm Outcomes After Infrapopliteal Interventions in Patients With Critical Limb Ischemia Based on the TASC II Classification of Below-the-Knee Arteries. J Endovasc Ther an Off J Int Soc Endovasc Spec. 2017 Jun;24(3):321–30.
10. Dayama A, Tsilimparis N, Kolakowski S, Matolo NM, Humphries MD. Clinical outcomes of bypass-first versus endovascular-first strategy in patients with chronic limb-threatening ischemia due to infrageniculate arterial disease. J Vasc Surg. 2019 Jan;69(1):156-163.e1.
11. Han X, Liao R, Li X, Zhang C, Huo S, Qin L, et al. Mesenchymal stem cells in treating human diseases : molecular mechanisms and clinical studies. 2025;(March).
12. Aulia A, Rismayani D, Nopiyanti T, Noli ZA, Maliza R. Jurnal Biologi Tropis Potential of Mesenchymal Stem Cells ( MSCs ) for Various Disease Therapy : Systematic Review. 2024;
13. 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 [Internet]. 2013;11(1):1. Available from: Journal of Translational Medicine
14. Rodríguez MLA, Mateus LC, Sossa CL, Bayona SMB, Alfonso V, David S, et al. A novel therapeutic management for diabetes patients with chronic limb ‑ threatening ischemia : comparison of autologous bone marrow mononuclear cells versus allogenic Wharton jelly ‑ derived mesenchymal stem cells. Stem Cell Res Ther [Internet]. 2023;1–17. Available from: https://doi.org/10.1186/s13287-023-03427-z
15. 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 Off J Middle East Soc Organ Transplant. 2013 Oct;11(5):435–9.
16. 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. 2008;23:106–15.
17. 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 [Internet]. 2011;92(1):26–36. Available from: http://dx.doi.org/10.1016/j.diabres.2010.12.010
18. 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 Jun;20(6):1280–6.
19. Mohammadzadeh S. Keshavarzi, A.; Alimoghaddam, K.; Larijani, B.; Ghavamzadeh, A.; Ahmadi, A. S.; Shojaeifard, A.; Ostadali, M. R.; Sharifi, A. M.; Amini, M. R.; Mahmoudian, A.; Fakhraei, H.; Aalaa, M.; Mohajeri-Tehrani, M. R. L. S. Therapeutic Outcomes of Transplanting Autologous Granulocyte Colony-stimulating Factor-mobilised Peripheral Mononuclear Cells in Diabetic Patients with Critical Limb Ischaemia. Exp Clin Endocrinol Diabetes [Internet]. 2013;121(01):48–53. Available from: http://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0032-1311646
20. Sojakova D, Kahle M, Husakova J, Fejfarova V, Sutoris K, Jarosikova R, et al. Efficacy of autologous cell therapy on limb salvage in patients with chronic limb- threatening ischemia : 16-year single-center experience. 2025;1:1–15.
21. Monaro S, West S, Gullick J. Making decisions about amputation for chronic limb threatening ischaemia. J Vasc Nurs [Internet]. 2024;42(1):65–73. Available from: https://www.sciencedirect.com/science/article/pii/S1062030323001000
22. Monaro S, West S, Gullick J. Chronic limb-threatening ischaemia and reframing the meaning of “end”. J Clin Nurs. 2021 Mar;30(5–6):687–700.
23. Gao W, Chen D, Liu G, Ran X. Autologous stem cell therapy for peripheral arterial disease : a systematic review and meta-analysis of randomized controlled trials. 2019;1–14.
24. Xie B, Luo H, Zhang Y, Wang Q, Zhou C, Xu D. Review Article Autologous Stem Cell Therapy in Critical Limb Ischemia : A Meta-Analysis of Randomized Controlled Trials. 2018;2018.
25. Kareti YB, Kumar V, Desai SC, Ramswamy CA, Gowda SS. Stem Cell Therapy in No Option Chronic Limb-threatening Ischemia. Indian J Vasc Endovasc Surg [Internet]. 2025;12(2). Available from: https://journals.lww.com/ijvs/fulltext/2025/04000/stem_cell_therapy_in_no_option_chronic.7.aspx
26. Huerta CT, Voza FA, Ortiz YY, Liu ZJ, Velazquez OC. Mesenchymal stem cell-based therapy for non-healing wounds due to chronic limb-threatening ischemia: A review of preclinical and clinical studies. Front Cardiovasc Med. 2023;10:1113982.
27. 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. 2013;48–53.
28. Navarro LVL, Chen X, Tatiana, Lady, Viviescas G, Roa AKA, Gonzalez MLL, et al. Mesenchymal stem cells for critical limb ischemia : their function , mechanism , and therapeutic potential. 2022;1–17.
29. Bagno LL, Salerno AG, Balkan W, Hare JM. Mechanism of action of mesenchymal stem cells (MSCs): Impact of Delivery Method. 2023;22(4):449–63.
30. Tebebi PA, Kim SJ, Williams RA, Milo B, Frenkel V, Burks SR, et al. Improving the therapeutic efficacy of mesenchymal stromal cells to restore perfusion in critical limb ischemia through pulsed focused ultrasound. Nat Publ Gr. 2017;(September 2016):1–11.
Published
2026-09-08
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How to Cite
Athoillah, N., Simanjuntak, A., As’Ar, M. C., Aryasatya, D., Sugiarto, L. A., Utomo, H., Aisya, M., Listiono, K., Negari, A. D., Hidayat, Y., & Maulana, A. (2026). Efficacy and Safety of Mesenchymal Stem Cell Therapy in Chronic Limb-Threatening Ischemia: A Meta-analysis of Randomized Controlled Trials. Indonesian Journal of Cardiology. https://doi.org/10.30701/ijc.1990
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