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DOI: 10.1055/s-0045-1809678
Mesenchymal Stem Cells for the Treatment of Complex Anovaginal and Rectovaginal Fistulas in Crohn's Disease: A Systematic Review
Funding The authors declare that no funds or other support was received during the preparation of this manuscript.

Abstract
Objective
To evaluate the efficacy and safety of mesenchymal stem cells (MSCs) for treating complex anovaginal and rectovaginal fistulas in Crohn's disease (CD) patients through a systematic review.
Methods
This review adhered to PRISMA and Cochrane guidelines. Literature searches were conducted on PubMed, Cochrane Library, Embase, and Web of Science using a PICO framework (P: CD patients with complex fistulas; I: MSC therapy; C: conventional treatments; O: efficacy and safety). Keywords included “stem cell,” “fistula,” and “Crohn's disease.” Articles were screened via the Rayyan® platform for inclusion based on eligibility criteria, with conflicts resolved by consensus.
Results
Of 1,197 records, 7 studies met inclusion criteria. MSC therapy demonstrated variable healing rates ranging from 50% to 75%, with low adverse event profiles. Studies highlighted therapeutic potential in reducing fistula drainage and promoting tissue regeneration. However, significant heterogeneity in patient populations, MSC doses, and study methodologies complicated outcome standardization. A meta-analysis reported fistula healing rates of 58–62% and clinical remission of 62.52%, superior to conventional therapies. Factors such as disease severity, prior treatments, and anatomical differences influenced outcomes.
Conclusions
MSCs offer promising treatment for complex fistulas in CD, demonstrating favorable safety and efficacy. However, variability in study designs, dosing protocols, and patient profiles underscores the need for standardized methodologies and larger clinical trials. Optimizing MSC use, particularly as a first-line therapy, could enhance outcomes and provide a viable alternative to conventional surgical approaches.
Author Contributions
Kleuber Arias Meireles Martins, Leonardo Januário Campos Cardoso, Mariana Menezes Corcinio, Isabela Coutinho Faria, and Pedro Henrique Gibram Gontijo were responsible for the conceptualization of the study. The methodology was developed by Kleuber Arias Meireles Martins, Leonardo Januário Campos Cardoso, and Mariana Menezes Corcinio. Software development was carried out by Kleuber Arias Meireles Martins, Leonardo Januário Campos Cardoso, and Isabela Coutinho Faria. Formal analysis was conducted by Ana Júlia da Silva Oliveira Bittarães and Bárbara Nogueira Braga, and Mariana Lisboa de Jesus. Writing, review, nd editing were done Kleuber Arias Meireles Martins and Leonardo Januário Campos. Supervision was provided by Kleuber Arias Meireles Martins and Leonardo Januário Campos. All authors have reviewed and approved the final version of the manuscript.
Publication History
Received: 26 January 2025
Accepted: 21 March 2025
Article published online:
30 June 2025
© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/)
Thieme Revinter Publicações Ltda.
Rua Rego Freitas, 175, loja 1, República, São Paulo, SP, CEP 01220-010, Brazil
Kleuber Arias Meireles Martins, Isabela Coutinho Faria, Leonardo Januário Campos Cardoso, Pedro Henrique Gibram Gontijo, Ana Júlia da Silva Oliveira Bittarães, Mariana Menezes Corcinio, Bárbara Nogueira Braga, Mariana Lisboa de Jesus. Mesenchymal Stem Cells for the Treatment of Complex Anovaginal and Rectovaginal Fistulas in Crohn's Disease: A Systematic Review. Journal of Coloproctology 2025; 45: s00451809678.
DOI: 10.1055/s-0045-1809678
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References
- 1 Cao Y, Su Q, Zhang B, Shen F, Li S. Efficacy of stem cells therapy for Crohn's fistula: a meta-analysis and systematic review. Stem Cell Res Ther 2021; 12 (01) 32
- 2 Yang F, Ni B, Liu Q. et al. Human umbilical cord-derived mesenchymal stem cells ameliorate experimental colitis by normalizing the gut microbiota. Stem Cell Res Ther 2022; 13 (01) 475
- 3 Lungaro L, Costanzini A, Manza F. et al. Impact of Female Gender in Inflammatory Bowel Diseases: A Narrative Review. J Pers Med 2023; 13 (02) 165
- 4 Seyedian SS, Nokhostin F, Malamir MD. A review of the diagnosis, prevention, and treatment methods of inflammatory bowel disease. J Med Life 2019; 12 (02) 113-122
- 5 Cockburn E, Kamal S, Chan A. et al. Crohn's disease: an update. Clin Med (Lond) 2023; 23 (06) 549-557
- 6 Panés J, Rimola J. Perianal fistulizing Crohn's disease: pathogenesis, diagnosis and therapy. Nat Rev Gastroenterol Hepatol 2017; 14 (11) 652-664
- 7 Iglay K, Bennett D, Kappelman MD. et al. A systematic review of the patient burden of Crohn's disease-related rectovaginal and anovaginal fistulas. BMC Gastroenterol 2022; 22 (01) 36
- 8 Lightner AL, Reese JS, Ream J. et al. A phase IB/IIA study of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of rectovaginal fistulizing Crohn's disease. Surgery 2024; 175 (02) 242-249
- 9 Radcliffe AG, Ritchie JK, Hawley PR, Lennard-Jones JE, Northover JM. Anovaginal and rectovaginal fistulas in Crohn's disease. Dis Colon Rectum 1988; 31 (02) 94-99
- 10 Wei J, Zhang Y, Chen C. et al. Efficacy and safety of allogeneic umbilical cord-derived mesenchymal stem cells for the treatment of complex perianal fistula in Crohn's disease: a pilot study. Stem Cell Res Ther 2023; 14 (01) 311
- 11 Parian AM, Obi M, Fleshner P, Schwartz DA. Management of Perianal Crohn's Disease. Am J Gastroenterol 2023; 118 (08) 1323-1331
- 12 Cochrane Training [Internet]. Cochrane Handbook for Systematic Reviews of Interventions. Available from: https://training-cochrane-org.accesdistant.sorbonne-universite.fr/handbook
- 13 Page MJ, McKenzie JE, Bossuyt PM. et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71
- 14 Lightner AL, Pineiro AO, Reese J. et al. Treatment effect of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of fistulizing Crohn's disease are durable at 12 months. Surgery 2024; 175 (04) 984-990 https://www-sciencedirect-com.accesdistant.sorbonne-universite.fr/science/article/abs/pii/S0039606023008474
- 15 Lightner AL, Dozois EJ, Dietz AB. et al. Matrix-delivered autologous mesenchymal stem cell therapy for refractory rectovaginal Crohn's fistulas. Inflamm Bowel Dis 2020; 26 (05) 670-677 https://academic-oup-com.accesdistant.sorbonne-universite.fr/ibdjournal/article/26/5/670/5586216?login=false
- 16 García-Arranz M, Herreros MD, González-Gómez C. et al. Treatment of Crohn's-related rectovaginal fistula with allogeneic expanded-adipose derived stem cells: a phase I–IIa clinical trial. Stem Cells Transl Med 2016; 5 (11) 1441-1446 https://pubmed-ncbi-nlm-nih-gov.accesdistant.sorbonne-universite.fr/27412883/
- 17 Nikolic M, Stift A, Reinisch W. et al. Allogeneic expanded adipose-derived stem cells in the treatment of rectovaginal fistulas in Crohn's disease. Colorectal Dis 2021; 23 (01) 153-158
- 18 Godoy-Brewer GM, Owodunni OP, Parian AM, Duraes LC, Selaru FM, Gearhart SL. Initial Clinical Outcomes Using Umbilical Cord-Derived Tissue Grafts to Repair Anovaginal Fistula. Dis Colon Rectum 2023; 66 (02) 299-305 https://journals-lww-com.accesdistant.sorbonne-universite.fr/dcrjournal/fulltext/2023/02000/Initial_Clinical_Outcomes_Using_Umbilical.19.aspx
- 19 Herreros MD, Garcia-Olmo D, Guadalajara H, Georgiev-Hristov T, Brandariz L, Garcia-Arranz M. Stem cell therapy: a compassionate use program in perianal fistula. Stem Cells Int 2019; 2019 (01) 6132340 https://onlinelibrary-wiley-com.accesdistant.sorbonne-universite.fr/doi/abs/10.1155/2019/6132340
- 20 Pogacnik JS, Salgado G. Perianal Crohn's Disease. Clin Colon Rectal Surg 2019; 32 (05) 377-385
- 21 El-Gazzaz G, Hull T, Mignanelli E, Hammel J, Gurland B, Zutshi M. Analysis of function and predictors of failure in women undergoing repair of Crohn's related rectovaginal fistula. J Gastrointest Surg 2010; 14 (05) 824-829
- 22 Meyer J, Ris F, Parkes M, Davies J. Rectovaginal Fistula in Crohn's Disease: When and How to Operate?. Clin Colon Rectal Surg 2022; 35 (01) 10-20 (revisão - Meyer et al 2022)
- 23 DeLeon MF, Hull TL. Treatment Strategies in Crohn's-Associated Rectovaginal Fistula. Clin Colon Rectal Surg 2019; 32 (04) 261-267 https://pmc-ncbi-nlm-nih-gov.accesdistant.sorbonne-universite.fr/articles/PMC6606313/#sec2
- 24 Hotouras A, Ribas Y, Zakeri S, Murphy J, Bhan C, Chan CL. Gracilis muscle interposition for rectovaginal and anovaginal fistula repair: a systematic literature review. Colorectal Dis 2015; 17 (02) 104-110 10.1111/codi.12791
- 25 Egal A, Etienney I, Atienza P. Endorectal Advancement Flap With Muscular Plication in Anovaginal and Anterior Perineal Fistulas. Ann Coloproctol 2021; 37 (03) 141-145 https://pmc-ncbi-nlm-nih-gov.accesdistant.sorbonne-universite.fr/articles/PMC8273710/
- 26 Lan N, Wu X, Shen B. Stem cell therapy: light in the tunnel for penetrating Crohn's disease. Gastroenterol Rep (Oxf) 2023; 11: goac085 10.1093/gastro/goac085
- 27 Garcia-Olmo D, Herreros D, Pascual I. et al. Expanded Adipose-Derived Stem Cells for the Treatment of Complex Perianal Fistula. Diseases of the Colon &. Rectum. 2009; 52 (01) 79-86
- 28 Kaimakliotis P, Simillis C, Harbord M, Kontovounisios C, Rasheed S, Tekkis PP. A Systematic Review Assessing Medical Treatment for Rectovaginal and Enterovesical Fistulae in Crohn's Disease. J Clin Gastroenterol 2016; 50 (09) 714-721
- 29 Scott NA, Nair A, Hughes LE. Anovaginal and rectovaginal fistula in patients with Crohn's disease. Br J Surg 1992; 79 (12) 1379-1380
- 30 Löffler T, Welsch T, Mühl S, Hinz U, Schmidt J, Kienle P. Long-term success rate after surgical treatment of anorectal and rectovaginal fistulas in Crohn's disease. Int J Colorectal Dis 2009; 24 (05) 521-526
- 31 Athanasiadis S, Yazigi R, Köhler A, Helmes C. Recovery rates and functional results after repair for rectovaginal fistula in Crohn's disease: a comparison of different techniques. Int J Colorectal Dis 2007; 22 (09) 1051-1060