gnckКолопроктологияKoloproktologia2073-75562686-7303Russian Association of Coloproctology10.33878/2073-7556-2024-23-3-100-111gnck-1948Research ArticleМЕТААНАЛИЗMETA-ANALYSISМезенхимальные стволовые клетки в лечении свищей перианальной области при болезни Крона (систематический обзор литературы и метаанализ)Mesenchymal stem cells for perianal fistulizing Crohn’s disease (systematic review and meta-analysis)https://orcid.org/0000-0002-9015-2600АносовИ. С.AnosovI. S.

Иван Сергеевич Аносов, к. м. н., заведующий отделом

123423; ул. Саляма Адиля, д. 2; Москва

Ivan S. Anosov

123423; Salyama Adilya st.; Moscow

https://orcid.org/0009-0004-6076-5192ЕрышоваТ. А.EryshovaT. A.

Татьяна Артемовна Ерышова, клинический ординатор

отделение малоинвазивной проктологии и тазовой хирургии

123423; ул. Саляма Адиля, д. 2; Москва

e-mail: teryshova.7@gmail.com

Tatyana A. Eryshova

123423; Salyama Adilya st.; Moscow

e-mail: teryshova.7@gmail.com

polikarpova-e@yandex.ruhttps://orcid.org/0000-0003-0556-1782ХрюкинР. Ю.KhryukinR. Yu.

Роман Юрьевич Хрюкин, к. м. н., старший научный сотрудник

отдел малоинвазивной проктологии

123423; ул. Саляма Адиля, д. 2; Москва

Roman Yu. Khryukin

123423; Salyama Adilya st.; Moscow

https://orcid.org/0000-0001-8413-8709ЗахаровМ. А.ZakharovM. A.

Марк Александрович Захаров, врач-колопроктолог

отделение малоинвазивной проктологии и тазовой хирургии

123423; ул. Саляма Адиля, д. 2; Москва

Mark A. Zakharov

123423; Salyama Adilya st.; Moscow

https://orcid.org/0000-0001-9294-5447АчкасовС. И.AchkasovS. I.

Сергей Иванович Ачкасов, д.м.н., профессор, член-корр. РАН, директор ФГБУ, профессор

кафедра колопроктологии

123423; ул. Саляма Адиля, д. 2; 125993; ул. Баррикадная, д. 2/1; Москва

Sergey I. Achkasov

123423; Salyama Adilya st.; 125993; Barrikadnaya st., 2/1; Moscow

ФГБУ «НМИЦ колопроктологии имени А.Н. Рыжих» Минздрава РоссииРоссияRyzhikh National Medical Research Center of ColoproctologyRussian FederationФГБУ «НМИЦ колопроктологии имени А.Н. Рыжих» Минздрава России; ФГБОУ ДПО РМАНПО Минздрава РоссииРоссияRyzhikh National Medical Research Center of Coloproctology; Russian Medical Academy of Continuous Professional EducationRussian Federation202421092024233100111Copyright © Аносов И.С., Ерышова Т.А., Хрюкин Р.Ю., Захаров М.А., Ачкасов С.И., 20242024Аносов И.С., Ерышова Т.А., Хрюкин Р.Ю., Захаров М.А., Ачкасов С.И.Anosov I.S., Eryshova T.A., Khryukin R.Y., Zakharov M.A., Achkasov S.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.ruproctology.com/jour/article/view/1948   ВВЕДЕНИЕ

   ВВЕДЕНИЕ: традиционные методы лечения перианальных проявлений болезни Крона (ППБК) связаны с высокой частотой рецидивов и осложнений. Местное применение мезенхимальных стволовых клеток (МСК) является перспективным направлением и альтернативой повторным операциям при ППБК. По данным литературы, применение МСК демонстрирует высокую частоту заживления прямокишечных свищей после однократной инъекции и характеризуется практически полным отсутствием побочных эффектов.

   ЦЕЛЬ

   ЦЕЛЬ: сравнить эффективность (заживление ППБК) и безопасность (частота осложнений) применения МСК и плацебо у пациентов с ППБК.

   ПАЦИЕНТЫ И МЕТОДЫ

   ПАЦИЕНТЫ И МЕТОДЫ: проведен систематический обзор литературы и метаанализ данных клинических исследований, сравнивающих однократное местное введение МСК при ППБК и плацебо. В метаанализ включено 5 рандомизированных клинических исследований и получены данные о результатах лечения 289 пациентов.

   РЕЗУЛЬТАТЫ

   РЕЗУЛЬТАТЫ: проведенный метаанализ демонстрирует высокую эффективность однократного местного введения МСК при ППБК в сравнении с плацебо (ОШ = 2,10, ДИ 1,28–3,46, p = 0,003). Наиболее часто встречающиеся послеоперационные осложнения (формирование абсцессов и дополнительных свищей), вероятно, связаны с естественным течением заболевания и между группами статистически значимо не различаются. На результаты оперативного лечения могут оказывать влияние: тип, источник и концентрация МСК, способ их доставки, а также количество инъекций.

   ЗАКЛЮЧЕНИЕ

   ЗАКЛЮЧЕНИЕ: местное применение мезенхимальных стволовых клеток — эффективный и безопасный метод лечения перианальных проявлений болезни Крона, однако наличие существенных ограничений в проведенном метаанализе заставляет осторожно относиться к полученным результатам и требует проведения дальнейших сравнительных рандомизированных исследований.

   AIM

   AIM: to compare the efficacy (fistulas healing rate) and safety (morbidity rate) of mesenchymal stem cells (MSC) and placebo in patients with perianal fistulizing Crohn’s disease (PFCD).

   PATIENTS AND METHODS

   PATIENTS AND METHODS: a systematic review and meta-analysis of clinical trials, comparing the results of treatment of PFCD with single local administration of MSCs or placebo was performed. The meta-analysis included 5 randomized clinical trials and the results of treatment of 289 patients were analyzed.

   RESULTS

   RESULTS: the meta-analysis demonstrates the high efficacy of a single local administration of MSCs for PFCD compared with placebo (OR = 2.10, CI 1.28–3.46, p = 0.003). The most common postoperative complications — abscesses and fistulas — are probably associated with the natural course of the disease and do not differ significantly between the groups. The results of surgery may be affected by the type, source and concentration of MSCs, the method of delivery and the number of injections.

   CONCLUSION

   CONCLUSION: local administration of mesenchymal stem cells is an effective and safe method for perianal fistulas in Crohn’s disease, however, the presence of significant limitations in the meta-analysis makes it cautious about the results obtained and requires further randomized trials.

мезенхимальные стволовые клеткисвищ прямой кишкисвищ перианальной областиболезнь Кронаперианальные проявления болезни КронаППБКМСКmesenchymal stem cellsanorectal fistulaperianal fistulaCrohn’s diseaseperianal fistulizing Crohn’s diseasePFCDMSCReferencesPark SH, Aniwan S, Scott Harmsen W, et al. Update on the natural course of fistulizing perianal Crohn’s disease in a population-based cohort. Inflamm Bowel Dis. 2019;25:1054–1060. doi: 10.1093/ibd/izy329Park SH, Aniwan S, Scott Harmsen W, et al. Update on the natural course of fistulizing perianal Crohn’s disease in a population-based cohort. Inflamm Bowel Dis. 2019;25:1054–1060. doi: 10.1093/ibd/izy329Peyrin-Biroulet L, Loftus EV, Colombel JF, et al. The natural history of adult Crohn’s disease in population-based cohorts. Am. J. Gastroenterol. 2010;105(2):289–297. doi: 10.1038/ajg.2009.579Peyrin-Biroulet L, Loftus EV, Colombel JF, et al. The natural history of adult Crohn’s disease in population-based cohorts. Am. J. Gastroenterol. 2010;105(2):289–297. doi: 10.1038/ajg.2009.579Schwartz DA, Loftus EV, Jr., Tremaine WJ, et al. The natural history of fistulizing Crohn’s disease in Olmsted County, Minnesota. Gastroenterology. 2002;122(4):875–880. doi: 10.1053/gast.2002.32362Schwartz DA, Loftus EV, Jr., Tremaine WJ, et al. The natural history of fistulizing Crohn’s disease in Olmsted County, Minnesota. Gastroenterology. 2002;122(4):875–880. doi: 10.1053/gast.2002.32362Panes J, Rimola J. Perianal fistulizing Crohn’s disease: pathogenesis, diagnosis and therapy. Nat Rev Gastroenterol Hepatol. 2017;14(11):652–664. doi: 10.1038/nrgastro.2017.104Panes J, Rimola J. Perianal fistulizing Crohn’s disease: pathogenesis, diagnosis and therapy. Nat Rev Gastroenterol Hepatol. 2017;14(11):652–664. doi: 10.1038/nrgastro.2017.104Siegmund B, Feakins RM, Barmias G, et al. Results of the Fifth Scientific Workshop of the ECCO (II): Pathophysiology of Perianal Fistulizing Disease. J Crohns Colitis. 2016;10(4):377–386. doi: 10.1093/ecco-jcc/jjv228Siegmund B, Feakins RM, Barmias G, et al. Results of the Fifth Scientific Workshop of the ECCO (II): Pathophysiology of Perianal Fistulizing Disease. J Crohns Colitis. 2016;10(4):377–386. doi: 10.1093/ecco-jcc/jjv228Eglinton TW, Barclay ML, Gearry RB, et al. The spectrum of perianal Crohn’s disease in a population-based cohort. Dis Colon Rectum. 2012;55:773–777. doi: 10.1097/DCR.0b013e31825228b0Eglinton TW, Barclay ML, Gearry RB, et al. The spectrum of perianal Crohn’s disease in a population-based cohort. Dis Colon Rectum. 2012;55:773–777. doi: 10.1097/DCR.0b013e31825228b0Molendijk I, Nuij VJ, van der Meulen-de Jong AE, et al. Disappointing durable remission rates in complex Crohn’s disease fistula. Inflamm Bowel Dis.2014;20(11):2022–2028. doi: 10.1097/MIB.0000000000000148Molendijk I, Nuij VJ, van der Meulen-de Jong AE, et al. Disappointing durable remission rates in complex Crohn’s disease fistula. Inflamm Bowel Dis.2014;20(11):2022–2028. doi: 10.1097/MIB.0000000000000148Аносов И.С., Нанаева Б.А., Варданян А.В., и соавт. Перианальные свищи при болезни Крона (обзор литературы). Колопроктология. 2023;22(1):128–137. doi: 10.33878/2073-7556-2023-22-1-128-137Anosov I.S., Nanaeva B.A., Vardanyan A.V., et al. Perianal fistulas in Crohn’s disease (review). Koloproctologia. 2023;22(1):128–137. (in Russ.). doi: 10.33878/2073-7556-2023-22-1-128-137Cadeddu F, Salis F, Lisi G, et al. Complex anal fistula remains a challenge for colorectal surgeon. Int J Color Dis. 2015;30:595–603. doi: 10.1007/s00384-014-2104-7Cadeddu F, Salis F, Lisi G, et al. Complex anal fistula remains a challenge for colorectal surgeon. Int J Color Dis. 2015;30:595–603. doi: 10.1007/s00384-014-2104-7Шелыгин Ю.А., Ивашкин В.Т., Ачкасов С.И., и соавт. Клинические рекомендации. Болезнь Крона (К50), взрослые. Колопроктология. 2023;22(3):10–49. doi: 10.33878/2073-7556-2023-22-3-10-49Shelygin Y.A., Ivashkin V.T., Achkasov S.I., et al. Clinical guidelines Crohn’s disease (К50), adults. Koloproctologia. 2023;22(3):10–49. (in Russ.). doi: 10.33878/2073-7556-2023-22-3-10-49Kamm MA, Ng SC. Perianal fistulizing Crohn’s disease: a call to action. Clin Gastroenterol Hepatol. 2008;6(1):7–10. doi: 10.1016/j.cgh.2007.10.010Kamm MA, Ng SC. Perianal fistulizing Crohn’s disease: a call to action. Clin Gastroenterol Hepatol. 2008;6(1):7–10. doi: 10.1016/j.cgh.2007.10.010Cowan CM, Shi YY, Aalami OO, et al. Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat Biotechnol. 2004;22(5):560–567. doi: 10.1038/nbt958Cowan CM, Shi YY, Aalami OO, et al. Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat Biotechnol. 2004;22(5):560–567. doi: 10.1038/nbt958Bor R, Fábián A, Farkas K, et al. Human mesenchymal stem cells therapy in the management of luminal and perianal fistulizing Crohn’s Disease — review of pathomechanism and existing clinical data. Expert Opin Biol Ther. 2018;18(7):737–745. doi: 10.1080/14712598.2018.1492543Bor R, Fábián A, Farkas K, et al. Human mesenchymal stem cells therapy in the management of luminal and perianal fistulizing Crohn’s Disease — review of pathomechanism and existing clinical data. Expert Opin Biol Ther. 2018;18(7):737–745. doi: 10.1080/14712598.2018.1492543Panés J, García-Olmo D, Van Assche G, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016;388(10051):1281–1290. doi: 10.1016/S0140-6736(16)31203-XPanés J, García-Olmo D, Van Assche G, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016;388(10051):1281–1290. doi: 10.1016/S0140-6736(16)31203-XPanés J, García-Olmo D, Van Assche G, et al. Long-term Efficacy and Safety of Stem Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients With Crohn’s Disease. Gastroenterology. 2018;154(5):1334–1342. doi: 10.1053/j.gastro.2017.12.020Panés J, García-Olmo D, Van Assche G, et al. Long-term Efficacy and Safety of Stem Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients With Crohn’s Disease. Gastroenterology. 2018;154(5):1334–1342. doi: 10.1053/j.gastro.2017.12.020Garcia-Olmo D, Gilaberte I, Binek M, et al. Follow-up Study to Evaluate the Long-term Safety and Efficacy of Darvadstrocel (Mesenchymal Stem Cell Treatment) in Patients With Perianal Fistulizing Crohn’s Disease: ADMIRE-CD Phase 3 Randomized Controlled Trial. Dis Colon Rectum. 2022;65(5):713–720. doi: 10.1097/DCR.0000000000002325Garcia-Olmo D, Gilaberte I, Binek M, et al. Follow-up Study to Evaluate the Long-term Safety and Efficacy of Darvadstrocel (Mesenchymal Stem Cell Treatment) in Patients With Perianal Fistulizing Crohn’s Disease: ADMIRE-CD Phase 3 Randomized Controlled Trial. Dis Colon Rectum. 2022;65(5):713–720. doi: 10.1097/DCR.0000000000002325Molendijk I, Bonsing BA, Roelofs H, et al. Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Promote Healing of Refractory Perianal Fistulas in Patients With Crohn’s Disease. Gastroenterology. 2015;149(4):918–927. doi: 10.1053/j.gastro.2015.06.014Molendijk I, Bonsing BA, Roelofs H, et al. Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Promote Healing of Refractory Perianal Fistulas in Patients With Crohn’s Disease. Gastroenterology. 2015;149(4):918–927. doi: 10.1053/j.gastro.2015.06.014Barnhoorn MC, Wasser MNJM, Roelofs H, et al. Long-term Evaluation of Allogeneic Bone Marrow-derived Mesenchymal Stromal Cell Therapy for Crohn’s Disease Perianal Fistulas. J Crohns Colitis. 2020;14(1):64–70. doi: 10.1093/ecco-jcc/jjz116Barnhoorn MC, Wasser MNJM, Roelofs H, et al. Long-term Evaluation of Allogeneic Bone Marrow-derived Mesenchymal Stromal Cell Therapy for Crohn’s Disease Perianal Fistulas. J Crohns Colitis. 2020;14(1):64–70. doi: 10.1093/ecco-jcc/jjz116Liberati A, Altman D, Tetzlaff J. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. doi: 10.1136/bmj.b2700Liberati A, Altman D, Tetzlaff J. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. doi: 10.1136/bmj.b2700Higgins JP, Altman DР, Gøtzsche PC. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Br Med J. 2011;343:889–893. doi: 10.1136/bmj.d5928Higgins JP, Altman DР, Gøtzsche PC. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Br Med J. 2011;343:889–893. doi: 10.1136/bmj.d5928Lee MJ, Heywood N, Adegbola S, et al. Systematic review of surgical interventions for Crohn’s anal fistula. BJS Open. 2017;1(3):55–66. doi: 10.1002/bjs5.13Lee MJ, Heywood N, Adegbola S, et al. Systematic review of surgical interventions for Crohn’s anal fistula. BJS Open. 2017;1(3):55–66. doi: 10.1002/bjs5.13Abramowitz L, Brochard C, Pigot F, et al. Surgical closure, mainly with glue injection and anti-tumour necrosis factor α, in fistulizing perianal Crohn’s disease: A multicentre randomized controlled trial. Colorectal Dis. 2022;24(2):210–219. doi: 10.1111/codi.15947Abramowitz L, Brochard C, Pigot F, et al. Surgical closure, mainly with glue injection and anti-tumour necrosis factor α, in fistulizing perianal Crohn’s disease: A multicentre randomized controlled trial. Colorectal Dis. 2022;24(2):210–219. doi: 10.1111/codi.15947Yao Y, Huang J, Geng Y, et al. Paracrine action of mesenchymal stem cells revealed by single cell gene profiling in infarcted murine hearts. PLoS One. 2015;10(6):129–164. doi: 10.1371/journal.pone.0129164Yao Y, Huang J, Geng Y, et al. Paracrine action of mesenchymal stem cells revealed by single cell gene profiling in infarcted murine hearts. PLoS One. 2015;10(6):129–164. doi: 10.1371/journal.pone.0129164Francois S, Bensidhoum M, Mouiseddine M, et al. Local irradiation not only induces homing of human mesenchymal stem cells at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution after irradiation damage. Stem Cells. 2006;24(4):1020–1029. doi: 10.1634/stemcells.2005-0260Francois S, Bensidhoum M, Mouiseddine M, et al. Local irradiation not only induces homing of human mesenchymal stem cells at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution after irradiation damage. Stem Cells. 2006;24(4):1020–1029. doi: 10.1634/stemcells.2005-0260Roda G, Jharap B, Neeraj N, et al. Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management. Clin Transl Gastroenterol. 2016;7(1):135. doi: 10.1038/ctg.2015.63Roda G, Jharap B, Neeraj N, et al. Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management. Clin Transl Gastroenterol. 2016;7(1):135. doi: 10.1038/ctg.2015.63Minozzi S, Bonovas S, Lytras T, et al. Risk of infections using anti-TNF agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis : a systematic review and meta-analysis. Expert Opin Drug Saf. 2016;15:11–34. doi: 10.1080/14740338.2016.1240783Minozzi S, Bonovas S, Lytras T, et al. Risk of infections using anti-TNF agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis : a systematic review and meta-analysis. Expert Opin Drug Saf. 2016;15:11–34. doi: 10.1080/14740338.2016.1240783Князев О.В., Парфенов А.И., Коноплянников А.Г., и соавт. Безопасность терапии воспалительных заболеваний кишечника с применением мезенхимальных стромальных клеток: результаты 5-летнего наблюдения. Терапевтический архив. 2015;2:39–44. doi: 10.17116/terarkh201587239-44Knyazev O.V., Parfenov A.I., Konoplyannikov A.G., et al. Safety of mesenchymal stromal cell therapy for inflammatory bowel diseases: Results of a 5-year follow-up. Terapevticheskii arkhiv. 2015;2:39–44. (in Russ.). doi: 10.17116/terarkh201587239-44Van Assche G, Dignass A, Reinisch W, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: Special situations. J Crohns Colitis. 2010;4(1):63–101. doi: 10.1016/j.crohns.2009.09.009Van Assche G, Dignass A, Reinisch W, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: Special situations. J Crohns Colitis. 2010;4(1):63–101. doi: 10.1016/j.crohns.2009.09.009Mueller MH, Geis M, Glatzle J, et al. Risk of fecal diversion in complicated perianal Crohn’s disease. J Gastrointest Surg. 2007;11(4):529–537. doi: 10.1007/s11605-006-0029-3Mueller MH, Geis M, Glatzle J, et al. Risk of fecal diversion in complicated perianal Crohn’s disease. J Gastrointest Surg. 2007;11(4):529–537. doi: 10.1007/s11605-006-0029-3Scott LJ. Darvadstrocel: A Review in Treatment-Refractory Complex Perianal Fistulas in Crohn’s Disease. BioDrugs. 2018;32(6):627–634. doi: 10.1007/s40259-018-0311-4Scott LJ. Darvadstrocel: A Review in Treatment-Refractory Complex Perianal Fistulas in Crohn’s Disease. BioDrugs. 2018;32(6):627–634. doi: 10.1007/s40259-018-0311-4Cao Y, Ding Z, Han C, et al. Efficacy of Mesenchymal Stromal Cells for Fistula Treatment of Crohn’s Disease : A Systematic Review and Meta-Analysis. Dig Dis Sci. 2017;62(4):851–860. doi: 10.1007/s10620-017-4453-xCao Y, Ding Z, Han C, et al. Efficacy of Mesenchymal Stromal Cells for Fistula Treatment of Crohn’s Disease : A Systematic Review and Meta-Analysis. Dig Dis Sci. 2017;62(4):851–860. doi: 10.1007/s10620-017-4453-xWang R, Yao Q, Chen W, et al. Stem cell therapy for Crohn’s disease : systematic review and meta-analysis of preclinical and clinical studies. Stem Cell Res Ther. 2021;12(1):463. doi: 10.1186/s13287-021-02533-0Wang R, Yao Q, Chen W, et al. Stem cell therapy for Crohn’s disease : systematic review and meta-analysis of preclinical and clinical studies. Stem Cell Res Ther. 2021;12(1):463. doi: 10.1186/s13287-021-02533-0Cho YB, Park KJ, Yoon SN, et al. Long-term results of adipose-derived stem cell therapy for the treatment of Crohn’s fistula. Stem Cells Transl Med. 2015;4(5):532–537. doi: 10.5966/sctm.2014-0199Cho YB, Park KJ, Yoon SN, et al. Long-term results of adipose-derived stem cell therapy for the treatment of Crohn’s fistula. Stem Cells Transl Med. 2015;4(5):532–537. doi: 10.5966/sctm.2014-0199Bernardo M, Avanzini M, Ciccocioppo R, et al. Phenotypical/functional characterization of in vitro-expanded mesenchymal stromal cells from patients with Crohn’s disease. Cytotherapy. 2009;7:825–836. doi: 10.3109/14653240903121260Bernardo M, Avanzini M, Ciccocioppo R, et al. Phenotypical/functional characterization of in vitro-expanded mesenchymal stromal cells from patients with Crohn’s disease. Cytotherapy. 2009;7:825–836. doi: 10.3109/14653240903121260Herreros MD, Garcia-Arranz M, Guadalajara H, et al. Autologous expanded adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistulas: a phase III randomized clinical trial (FATT 1: fistula Advanced Therapy Trial 1) and long-term evaluation. Dis Colon Rectum. 2012;55(7):762–772. doi: 10.1097/DCR.0b013e318255364aHerreros MD, Garcia-Arranz M, Guadalajara H, et al. Autologous expanded adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistulas: a phase III randomized clinical trial (FATT 1: fistula Advanced Therapy Trial 1) and long-term evaluation. Dis Colon Rectum. 2012;55(7):762–772. doi: 10.1097/DCR.0b013e318255364aStroumza N, Fuzco G, Laporte J, et al. Surgical treatment of trans-sphincteric anal fistulas with the Fat GRAFT technique: a minimally invasive procedure. Colorectal Dis. 2017;19(8):316–319. doi: 10.1111/codi.13782Stroumza N, Fuzco G, Laporte J, et al. Surgical treatment of trans-sphincteric anal fistulas with the Fat GRAFT technique: a minimally invasive procedure. Colorectal Dis. 2017;19(8):316–319. doi: 10.1111/codi.13782Tutino R, Di Franco S, Massani M, et al. Autologous adipose-derived stromal vascular fraction and platelet concentrates for the treatment of complex perianal fistulas. Tech Coloproctol. 2023;27(2):135–143. doi: 10.1007/s10151-022-02675-0Tutino R, Di Franco S, Massani M, et al. Autologous adipose-derived stromal vascular fraction and platelet concentrates for the treatment of complex perianal fistulas. Tech Coloproctol. 2023;27(2):135–143. doi: 10.1007/s10151-022-02675-0Ascanelli S, Zamboni P, Campioni D, et al. Efficacy and Safety of Treatment of Complex Idiopathic Fistula-in-Ano Using Autologous Centrifuged Adipose Tissue Containing Progenitor Cells: A Randomized Controlled Trial. Dis Colon Rectum. 2021;64(10):1276–1285. doi: 10.1097/DCR.0000000000001924Ascanelli S, Zamboni P, Campioni D, et al. Efficacy and Safety of Treatment of Complex Idiopathic Fistula-in-Ano Using Autologous Centrifuged Adipose Tissue Containing Progenitor Cells: A Randomized Controlled Trial. Dis Colon Rectum. 2021;64(10):1276–1285. doi: 10.1097/DCR.0000000000001924Garcia-Olmo D, Herreros D, Pascual I, et al. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum. 2009;52(1):79–86. doi: 10.1007/DCR.0b013e3181973487Garcia-Olmo D, Herreros D, Pascual I, et al. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum. 2009;52(1):79–86. doi: 10.1007/DCR.0b013e3181973487Dozois EJ, Lightner AL, Dietz AB, et al. Durable Response in Patients With Refractory Fistulizing Perianal Crohn’s Disease Using Autologous Mesenchymal Stem Cells on a Dissolvable Matrix: Results from the Phase I Stem Cell on Matrix Plug Trial. Dis Colon Rectum. 2023;66(2):243–252. doi: 10.1097/DCR.0000000000002579Dozois EJ, Lightner AL, Dietz AB, et al. Durable Response in Patients With Refractory Fistulizing Perianal Crohn’s Disease Using Autologous Mesenchymal Stem Cells on a Dissolvable Matrix: Results from the Phase I Stem Cell on Matrix Plug Trial. Dis Colon Rectum. 2023;66(2):243–252. doi: 10.1097/DCR.0000000000002579Dige A, Hougaard HT, Agnholt J, et al. Efficacy of Injection of Freshly Collected Autologous Adipose Tissue Into Perianal Fistulas in Patients With Crohn’s Disease. Gastroenterology. 2019;156(8):2208–2216. doi: 10.1053/j.gastro.2019.02.005Dige A, Hougaard HT, Agnholt J, et al. Efficacy of Injection of Freshly Collected Autologous Adipose Tissue Into Perianal Fistulas in Patients With Crohn’s Disease. Gastroenterology. 2019;156(8):2208–2216. doi: 10.1053/j.gastro.2019.02.005Lee WY, Park KJ, Cho YB, et al. Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn’s fistula. Stem Cells. 2013;31(11):2575–2581. doi: 10.1002/stem.1357Lee WY, Park KJ, Cho YB, et al. Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn’s fistula. Stem Cells. 2013;31(11):2575–2581. doi: 10.1002/stem.1357Lightner AL, Wang Z, Zubair AC, et al. A Systematic Review and Meta-analysis of Mesenchymal Stem Cell Injections for the Treatment of Perianal Crohn’s Disease: Progress Made and Future Directions. Dis Colon Rectum. 2018;61(5):629–640. doi: 10.1097/DCR.0000000000001093Lightner AL, Wang Z, Zubair AC, et al. A Systematic Review and Meta-analysis of Mesenchymal Stem Cell Injections for the Treatment of Perianal Crohn’s Disease: Progress Made and Future Directions. Dis Colon Rectum. 2018;61(5):629–640. doi: 10.1097/DCR.0000000000001093Cao Y, Su Q, Zhang B, et al. Efficacy of stem cells therapy for Crohn’s fistula : a meta-analysis and systematic review. Stem Cell Res Ther. 2021;12(1):32. doi: 10.1186/s13287-020-02095-7Cao Y, Su Q, Zhang B, et al. Efficacy of stem cells therapy for Crohn’s fistula : a meta-analysis and systematic review. Stem Cell Res Ther. 2021;12(1):32. doi: 10.1186/s13287-020-02095-7Hamamoto H, Gorman JH 3<sup>rd</sup>, Ryan LP, et al. Allogeneic mesenchymal precursor cell therapy to limit remodeling after myocardial infarction: the effect of cell dosage. Ann Thorac Surg. 2009;87(3):794–801. doi: 10.1016/j.athoracsur.2008.11.057Hamamoto H, Gorman JH 3<sup>rd</sup>, Ryan LP, et al. Allogeneic mesenchymal precursor cell therapy to limit remodeling after myocardial infarction: the effect of cell dosage. Ann Thorac Surg. 2009;87(3):794–801. doi: 10.1016/j.athoracsur.2008.11.057Cheng F, Huang Z, Li Z. Mesenchymal stem-cell therapy for perianal fistulas in Crohn’s disease : a systematic review and meta-analysis. Tech Coloproctol. 2019;23(7):613–623. doi: 10.1007/s10151-019-02024-8Cheng F, Huang Z, Li Z. Mesenchymal stem-cell therapy for perianal fistulas in Crohn’s disease : a systematic review and meta-analysis. Tech Coloproctol. 2019;23(7):613–623. doi: 10.1007/s10151-019-02024-8Ciccocioppo R, Gallia A, Sgarella A, et al. Long-term follow-up of Crohn disease fistulas after local injections of bone marrow-derived mesenchymal stem cells. Mayo Clin Proc. 2015;90:747–755. doi: 10.1016/j.mayocp.2015.03.023Ciccocioppo R, Gallia A, Sgarella A, et al. Long-term follow-up of Crohn disease fistulas after local injections of bone marrow-derived mesenchymal stem cells. Mayo Clin Proc. 2015;90:747–755. doi: 10.1016/j.mayocp.2015.03.023Vapniarsky N, Arzi B, Hu JC, et al. Concise Review: Human Dermis as an Autologous Source of Stem Cells for Tissue Engineering and Regenerative Medicine. Stem Cells Transl Med. 2015;4(10):1187–1198. doi: 10.5966/sctm.2015-0084Vapniarsky N, Arzi B, Hu JC, et al. Concise Review: Human Dermis as an Autologous Source of Stem Cells for Tissue Engineering and Regenerative Medicine. Stem Cells Transl Med. 2015;4(10):1187–1198. doi: 10.5966/sctm.2015-0084Crop MJ, Baan CC, Korevaar SS, et al. Human adipose tissue-derived mesenchymal stem cells induce explosive T-cell proliferation. Stem Cells Dev. 2010;19(12):1843–1853. doi: 10.1089/scd.2009.0368Crop MJ, Baan CC, Korevaar SS, et al. Human adipose tissue-derived mesenchymal stem cells induce explosive T-cell proliferation. Stem Cells Dev. 2010;19(12):1843–1853. doi: 10.1089/scd.2009.0368Cohen CA, Shea AA, Heffron CL, et al. Intra-abdominal fat depots represent distinct immunomodulatory microenvironments: a murine model. PLoS One. 2013;8(6):664–677. doi: 10.1371/journal.pone.0066477Cohen CA, Shea AA, Heffron CL, et al. Intra-abdominal fat depots represent distinct immunomodulatory microenvironments: a murine model. PLoS One. 2013;8(6):664–677. doi: 10.1371/journal.pone.0066477Strioga M, Viswanathan S, Darinskas A, et al. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 2012;21(14):2724–2752. doi: 10.1089/scd.2011.0722Strioga M, Viswanathan S, Darinskas A, et al. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 2012;21(14):2724–2752. doi: 10.1089/scd.2011.0722Гатиатулина Е.Р., Мантурова Н.Е., Димов Г.П., и соавт. Стромально-васкулярная фракция жировой ткани: механизм действия, перспективы и риски местного применения. Пластическая хирургия и эстетическая медицина. 2019;2:43–48. doi: 10.17116/plast.hirurgia201902143Gatiatulina E.R., Manturova N.Е., Dimov G.P., et al. Adipose-derived stromal vascular fraction: mechanism of action, prospects and risks of local application. Plastic surgery and aesthetic medicine. 2019;2:43–48. (in Russ.). doi: 10.17116/plast.hirurgia201902143Liao HT, Chen CT. Osteogenic potential: Comparison between bone marrow and adipose-derived mesenchymal stem cells. World J Stem Cells. 2014;6(3):288–295. doi: 10.4252/wjsc.v6.i3.288Liao HT, Chen CT. Osteogenic potential: Comparison between bone marrow and adipose-derived mesenchymal stem cells. World J Stem Cells. 2014;6(3):288–295. doi: 10.4252/wjsc.v6.i3.288Johal KS, Lees VC, Reid AJ. Adipose-derived stem cells: selecting for translational success. Regen. Med. 2015;10(1):79–96. doi: 10.2217/rme.14.72Johal KS, Lees VC, Reid AJ. Adipose-derived stem cells: selecting for translational success. Regen. Med. 2015;10(1):79–96. doi: 10.2217/rme.14.72Mizuno H, Tobita M, Uysal AC. Concise review: Adipose-derived stem cells as a novel tool for future regenerative medicine. Stem Cells. 2012;30(5):804–810. doi: 10.1002/stem.1076Mizuno H, Tobita M, Uysal AC. Concise review: Adipose-derived stem cells as a novel tool for future regenerative medicine. Stem Cells. 2012;30(5):804–810. doi: 10.1002/stem.1076Minteer DM, Marra KG, Rubin JP. Adipose stem cells: biology, safety, regulation, and regenerative potential. Clin Plast Surg. 2015;42(2):169–179. doi: 10.1016/j.cps.2014.12.007Minteer DM, Marra KG, Rubin JP. Adipose stem cells: biology, safety, regulation, and regenerative potential. Clin Plast Surg. 2015;42(2):169–179. doi: 10.1016/j.cps.2014.12.007Zhou C, Li M, Zhang Y, et al. Autologous adipose-derived stem cells for the treatment of Crohn’s fistula-in-ano: an open-label, controlled trial. Stem Cell Res Ther. 2020;11(1):124. doi: 10.1186/s13287-020-01636-4Zhou C, Li M, Zhang Y, et al. Autologous adipose-derived stem cells for the treatment of Crohn’s fistula-in-ano: an open-label, controlled trial. Stem Cell Res Ther. 2020;11(1):124. doi: 10.1186/s13287-020-01636-4Laureti S, Gionchetti P, Cappelli A, et al. Refractory Complex Crohn’s Perianal Fistulas: A Role for Autologous Microfragmented Adipose Tissue Injection. Inflamm Bowel Dis. 2020;26(2):321–330. doi: 10.1093/ibd/izz051Laureti S, Gionchetti P, Cappelli A, et al. Refractory Complex Crohn’s Perianal Fistulas: A Role for Autologous Microfragmented Adipose Tissue Injection. Inflamm Bowel Dis. 2020;26(2):321–330. doi: 10.1093/ibd/izz051Gallo G, Tiesi V, Fulginiti S, et al. Mesenchymal Stromal Cell Therapy in the Management of Perianal Fistulas in Crohn’s Disease: An Up-To-Date Review. Medicina (Kaunas). 2020;56(11):563. doi: 10.3390/medicina56110563Gallo G, Tiesi V, Fulginiti S, et al. Mesenchymal Stromal Cell Therapy in the Management of Perianal Fistulas in Crohn’s Disease: An Up-To-Date Review. Medicina (Kaunas). 2020;56(11):563. doi: 10.3390/medicina56110563

The authors declare that there are no conflicts of interest present.