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中华细胞与干细胞杂志(电子版)

中华细胞与干细胞杂志(电子版) ›› 2023, Vol. 13 ›› Issue (03) : 172 -177. doi: 10.3877/cma.j.issn.2095-1221.2023.03.007

综述

间充质干细胞在克罗恩病肛瘘治疗中的研究进展
秦富豪, 郑正, 江滨†()   
  1. 210029　南京中医药大学研究生院
    210022　南京中医药大学附属南京中医院肛肠科
  • 收稿日期:2023-04-13 出版日期:2023-06-01
  • 通信作者: 江滨
  • 基金资助:
    2022年江苏省科技计划专项资金重点研发计划社会发展面上项目(BE2022674); 江苏省研究生科研与实践创新计划(SJCX210747)

Research progress of mesenchymal stem cells in the treatment of perianal fifistulizing Crohn's disease

Fuhao Qin, Zheng Zheng, Bin Jiang†()   

  1. Nanjing University of Chinese Medicine, Nanjing 210029, China
    Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, China
  • Received:2023-04-13 Published:2023-06-01
  • Corresponding author: Bin Jiang
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秦富豪, 郑正, 江滨. 间充质干细胞在克罗恩病肛瘘治疗中的研究进展[J]. 中华细胞与干细胞杂志(电子版), 2023, 13(03): 172-177.

Fuhao Qin, Zheng Zheng, Bin Jiang. Research progress of mesenchymal stem cells in the treatment of perianal fifistulizing Crohn's disease[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2023, 13(03): 172-177.

克罗恩病肛瘘（PFCD）目前多采用药物联合外科手术治疗，但常面临术后肛门失禁和愈合缓慢等难题。研究发现，间充质干细胞（MSCs）治疗PFCD安全有效，不仅可提高瘘管愈合率，而且可有效规避常规治疗带来不良反应，具有广泛的应用前景。本文就MSCs治疗PFCD机制及临床应用中的研究进展做一综述，以期为今后的研究奠定基础。

关键词: 间充质干细胞, 克罗恩病, 肛瘘, 研究进展

Perianal fifistulizing Crohn's disease (PFCD) is currently treated with drugs and surgery, however, it has problems such as anal incontinence and slow healing. Studies have found that mesenchymal stem cells (MSCs) are safe and effective in treating PFCD, which not only improve the healing rate of fistula, but also effectively avoid adverse reactions such as anal incontinence caused by conventional treatment, and have broad application prospects. This article reviews the research progress in the mechanism and clinical application of MSCs in treating of PFCD to lay a foundation for future research.

Key words: Mesenchymal stem cells, Crohn's disease, Perianal fistulizing, Research progress
表1 自体脂肪MSCs治疗克罗恩病肛瘘疗效
作者 年份 国家 样本量 干细胞类型 给药方法及途径 评估时间 效果
Garcia[15] 2005 西班牙 4 自体脂肪MSCs 局部注射（3 ~ 30）×106个MSCs 8周 75%（6/8）瘘管实现完全愈合，25%（2/8）得到缓解
Garcia[30] 2009 西班牙 49 自体脂肪MSCs 局部注射2×106个MSCs+纤维蛋白胶或单独注射纤维蛋白胶；第8周未愈合者，给予4×106个MSCs 8周 细胞治疗组71%（17/24）瘘管实现完全闭合，而纤维蛋白胶组16%（4/25）瘘管完全闭合
Cho[16] 2013 韩国 10 自体脂肪MSCs 根据瘘管的大小，局部注射1×107，2×107，4×107个MSCs 8周 共有30%（3/10）的患者瘘管实现完全闭合，70%（7/10）的患者得到缓解
Lee[29] 2013 韩国 33 自体脂肪MSCs 每1 cm瘘管长度局部注射3×107或6×107个MSCs 8周 82% （27/33）的患者瘘管实现完全闭合；88 % （23/26）第12月时瘘管完全闭合
Cho[40] 2015 韩国 24 自体脂肪MSCs 基于瘘管长度局部注射（9 ~ 42）× 107个MSCs 8周 83% （20/24）的患者瘘管实现完全闭合
Dietz[35] 2017 美国 12 自体脂肪MSCs 附着可吸收基质置入肛瘘2×107个MSCs 26周 83% （10/12）的瘘管实现完全愈合
Wainstein[41] 2018 智利 9 自体脂肪MSCs （10 ~ 12）×109个MSCs及富血小板血浆的混合剂 31个月 91% （10/11）的瘘管完全愈合，9% （1/11）部分愈合
江滨[18] 2019 中国 23 自体脂肪MSCs 局部注射（142.3 ± 45.7）×106个MSCs 3个月 观察组90.91% （10/11）的瘘管实现完全闭合，对照45.5% （5/11）的瘘管完全闭合
Cho[42] 2021 韩国 5 自体脂肪MSCs 当瘘管直径小于1 cm时注射3×107个MSCs，当瘘管直径大于1 cm且小于等于2 cm时注射6×107个MSCs 8周 80% （4/5）的瘘管实现完全闭合，20% （1/5）的瘘管引流减少
Dozois[43] 2023 美国 20 自体脂肪MSCs 附着可吸收生物基质后置入瘘管内2×107个MSCs 6个月 77% （14/18）的患者瘘管实现完全闭合，术后12个月72.% （13/18）的瘘管完全闭合
表2 异体脂肪MSCs治疗克罗恩病肛瘘的疗效
作者 年份 国家 样本量 干细胞类型 给药方法及途径 评估时间 效果
Portilla[31] 2013 西班牙 24 异体脂肪MSCs 局部注射20×106个MSCs；12周不愈合者，给予2倍细胞量2次注射 24周 56.3% （9/16）的患者瘘管实现了完全闭合
Panes[17] 2016 西班牙 212 异体脂肪MSCs 局部注射1.2×109个MSCs 24周 实验组中50% （53/107）的患者症状缓解，对照组中34% （36/105）得到缓解
Park[44] 2016 韩国 6 异体脂肪MSCs 根据瘘道大小分别局部注射4.33×107、17×107个MSCs 34周 50% （3/6）的瘘管实现完全闭合
Schwandner[45] 2021 德国 12 异体脂肪MSCs 局部注射5×106个MSCs 14.3个月 66.7% （8/12）的患者瘘管实现完全闭合，33.3% （4/12）瘘管引流减少
Furukawa[46] 2022 日本 22 异体脂肪MSCs 局部注射12×107个MSCs 24周 59.1% （13/22）的患者瘘管实现完全闭合
Garcia[47] 2022 西班牙 40 异体脂肪MSCs 局部注射12×107个MSCs 104周 实验组56% （14/25）的患者实现临床缓解，对照组40% （6/15）得到临床缓解
Colombo[48] 2022 意大利 3 异体脂肪MSCs 局部注射1.2×108个MSCs 1个月 无患者瘘管实现完全闭合，但症状均得到了明显改善
表3 骨髓MSCs治疗克罗恩病肛瘘的疗效
作者 年份 国家 样本量 干细胞类型 给药方法及途径 评估时间 效果
Ciccocioppo[49] 2011 意大利 10 自体骨髓MSCs 局部注射（1.5 ~ 3）×107个MSCs 52周 70% （7/10）瘘管实现完全愈合，30%（3/10）的患者得到缓解
Ciccocioppo[50] 2015 意大利 8 异体骨髓MSCs 局部注射2×107和4×107个MSCs 12个月 88%瘘管实现完全愈合
Molendijk[28] 2015 荷兰 15 异体骨髓MSCs 局部注射1×107或3×107或9×107个MSCs 24周 53% （8/15）的患者瘘管实现完全愈合，且低剂量疗效优于高剂量
Vosough[32] 2022 伊朗 5 自体骨髓MSCs联合纤维蛋白胶 每4周注射4次瘘管内细胞，每1次含有4×107个MSCs的纤维蛋白胶中 6个月 20% （1/5）的患者瘘管实现完全闭合，60% （3/5）部分缓解
Reenaers[51] 2023 比利时 16 异体骨髓MSCs 局部注射3×107个MSCs 12周 56% （9/16）瘘管实现完全闭合
Lightner[33] 2023 美国 23 异体骨髓MSCs 局部注射7.5×107个MSCs，如果未完全愈合，则在3月后再次注射7.5×107个MSCs 6个月 治疗组83% （15/18）的患者瘘管实现完全闭合，对照组40% （2/5）的瘘管实现完全闭合
1
Cushing K, Higgins P. Management of Crohn disease: a review[J]. JAMA, 2021, 325(1):69-80.
2
Ng SC, Tang W, Ching JY, et al. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn's and colitis epidemiology study[J]. Gastroenterology, 2013, 145(1):158-165.
3
Park SH, Aniwan S, Scott Harmsen W, et al. Update on the natural course of fistulizing perianal Crohn's disease in a population-based cohort[J]. Inflamm Bowel Dis, 2019, 25(6):1054-1060.
4
Costela-Ruiz VJ, Melguizo-Rodriguez L, Bellotti C, et al. Different sources of mesenchymal stem cells for tissue regeneration: a guide to identifying the most favorable one in orthopedics and dentistry applications[J]. Int J Mol Sci, 2022, 23(11):6356. doi: 10.3390/ijms23116356.
5
Widjaja G, Jalil AT, Budi HS, et al. Mesenchymal stromal/stem cells and their exosomes application in the treatment of intervertebral disc disease: a promising frontier[J]. Int Immunopharmacol, 2022, 105:108537. doi: 10.1016/j.intimp.2022.108537.
6
Matta A, Nader V, Lebrin M, et al. Pre-conditioning methods and novel approaches with mesenchymal stem cells therapy in cardiovascular disease[J]. Cells, 2022, 11(10):1620. doi: 10.3390/cells11101620.
7
Bian D, Wu Y, Song G, et al. The application of mesenchymal stromal cells (MSCs) and their derivative exosome in skin wound healing: a comprehensive review[J]. Stem Cell Res Ther, 2022, 13(1):24. doi: 10.1186/s13287-021-02697-9.
8
Lu D, Xu Y, Liu Q, et al. Mesenchymal stem cell-macrophage crosstalk and maintenance of inflammatory microenvironment homeostasis[J]. Front Cell Dev Biol, 2021, 9:681171. doi: 10.3389/fcell.2021.681171.
9
Weiss ARR, Dahlke MH. Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs[J]. Front Immunol, 2019, 10:1191. doi: 10.3389/fimmu.2019.01191.
10
Al-Ghadban S, Bunnell BA. Adipose tissue-derived stem cells: immunomodulatory effects and therapeutic potential[J]. Physiology (Bethesda), 2020, 35(2):125-133.
11
Huang Y, Wu Q, Tam P. Immunomodulatory mechanisms of mesenchymal stem cells and their potential clinical applications[J]. Int J Mol Sci, 2022, 23(17):10023. doi: 10.3390/ijms231710023.
12
Zhou Y, Yamamoto Y, Xiao Z, et al. The Immunomodulatory functions of mesenchymal stromal/stem cells mediated via paracrine activity[J]. J Clin Med, 2019, 8(7):1025. doi: 10.3390/jcm8071025.
13
Kuca-Warnawin E, Janicka I, Szczesny P, et al. Modulation of T-cell activation markers expression by the adipose tissue-derived mesenchymal stem cells of patients with rheumatic diseases[J]. Cell Transplant, 2020, 29:2138938386. doi:10.1177/0963689720945682.
14
Krawczenko A, Klimczak A. Adipose tissue-derived mesenchymal stem/stromal cells and their contribution to angiogenic processes in tissue regeneration[J]. Int J Mol Sci, 2022, 23(5):2425. doi: 10.3390/ijms23052425.
15
Garcia-Olmo D, Garcia-Arranz M, Herreros D, et al. A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation[J]. Dis Colon Rectum, 2005, 48(7):1416-1423.
16
Cho YB, Lee WY, Park KJ, et al. Autologous adipose tissue-derived stem cells for the treatment of Crohn's fistula: a phase I clinical study[J]. Cell Transplant, 2013, 22(2):279-285.
17
Panes J, Garcia-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[J]. Lancet, 2016, 388(10051):1281-1290.
18
江滨，时宏珍，史央，等. 自体脂肪干细胞移植治疗复杂性肛瘘的临床观察[J]. 中华结直肠疾病电子杂志, 2019, 8(6):566-573.
19
Zhou 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[J]. Stem Cell Res Ther, 2020, 11(1):124. doi: 10.1186/s13287-020-01636-4.
20
章阳，江滨，王业皇，等. 自体脂肪干细胞治疗复杂性腺源性肛瘘的疗效[J]. 江苏医药, 2019, 45(9):890-892.
21
Gaertner WB, Burgess PL, Davids JS, et al. The American society of colon and rectal surgeons clinical practice guidelines for the management of anorectal abscess, fistula-in-ano, and rectovaginal fistula[J]. Dis Colon Rectum, 2022, 65(8):964-985.
22
Aust L, Devlin B, Foster SJ, et al. Yield of human adipose-derived adult stem cells from liposuction aspirates[J]. Cytotherapy, 2004, 6(1):7-14.
23
Avivar-Valderas A, Martín-Martín C, Ramírez C, et al. Dissecting allo-sensitization after local administration of human allogeneic adipose mesenchymal stem cells in perianal fistulas of Crohn's disease patients[J]. Front Immunol, 2019, 10:1244. doi: 10.3389/fimmu.2019.01244.
24
Roncoroni L, Gori R, Elli L, et al. Nutrition in patients with inflammatory bowel diseases: a narrative review[J]. Nutrients, 2022, 14(4):751. doi: 10.3390/nu14040751.
25
Zhang J, Lv S, Liu X, et al. Umbilical cord mesenchymal stem cell treatment for Crohn's disease: a randomized controlled clinical trial[J]. Gut Liver, 2018, 12(1):73-78.
26
Godoy-Brewer GM, Owodunni OP, Parian AM, et al. Initial clinical outcomes using umbilical cord-derived tissue grafts to repair anovaginal fistula[J]. Dis Colon Rectum, 2023, 66(2):299-305.
27
Barnhoorn MC, Wasser M, Roelofs H, et al. Long-term evaluation of allogeneic bone marrow-derived mesenchymal stromal cell therapy for Crohn's disease perianal fistulas[J]. J Crohns Colitis, 2020, 14(1):64-70.
28
Molendijk 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[J]. Gastroenterology, 2015, 149(4):918-927.
29
Lee WY, Park KJ, Cho YB, et al. Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn's fistula[J]. Stem Cells, 2013, 31(11):2575-2581.
30
Garcia-Olmo D, Herreros D, Pascual I, et al. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phaseⅡ clinical trial[J]. Dis Colon Rectum, 2009, 52(1):79-86.
31
de la Portilla F, Alba F, Garcia-Olmo D, et al. Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn's disease: results from a multicenter phase Ⅰ/Ⅱ a clinical trial[J]. Int J Colorectal Dis, 2013, 28(3):313-323.
32
Vosough M, Nikfam S, Torabi SH, et al. Mesenchymal stromal cell therapy improves refractory perianal fistula in Crohn's disease: case series clinical interventional study[J]. Cell J, 2022, 24(2):62-68.
33
Lightner AL, Reese J, Ream J, et al. A phase IB/IIA study of ex vivo expanded allogeneic bone marrow derived mesenchymal stem cells for the treatment of perianal fistulizing Crohn's disease[J]. Dis Colon Rectum, 2023. doi:10.1097/DCR.0000000000002567.
34
Szydlak R. Biological, chemical and mechanical factors regulating migration and homing of mesenchymal stem cells[J]. World J Stem Cells, 2021, 13(6):619-631.
35
Dietz AB, Dozois EJ, Fletcher JG, et al. Autologous mesenchymal stem cells, applied in a bioabsorbable matrix, for treatment of perianal fistulas in patients with Crohn's disease[J]. Gastroenterology, 2017, 153(1):59-62.
36
Molendijk I, van der Meulen De Jong AE, Verspaget HW, et al. Standardization of mesenchymal stromal cell therapy for perianal fistulizing Crohn's disease[J]. Eur J Gastroenterol Hepatol, 2018, 30(10):1148-1154.
37
Li X, Fan Q, Peng X, et al. Mesenchymal/stromal stem cells: necessary factors in tumour progression[J]. Cell Death Discov, 2022, 8(1):333.doi:10.1038/s41420-022-01107-0.
38
Tang RJ, Shen SN, Zhao XY, et al. Mesenchymal stem cells-regulated treg cells suppress colitis-associated colorectal cancer[J]. Stem Cell Res Ther, 2015, 6(1):71.doi: 10.1186/s13287-015-0055-8.
39
周影，周春根，江滨. 生物光学成像技术在干细胞应用中的研究进展[J]. 中华细胞与干细胞杂志（电子版）, 2021,11（3）:189-192.
40
Cho YB, Park KJ, Yoon SN, et al. Long-term results of adipose-derived stem cell therapy for the treatment of Crohn's fistula[J]. Stem Cells Transl Med, 2015, 4(5):532-537.
41
Wainstein C, Quera R, Fluxa D, et al. Stem cell therapy in refractory perineal Crohn's disease: long-term follow-up[J]. Colorectal Dis, 2018.doi:10.1111/codi.14002.
42
Cho YJ, Kwon H, Kwon YJ, et al. Efficacy and safety of autologous adipose tissue-derived stem cell therapy for children with refractory Crohn's complex fistula: a PhaseⅣclinical study[J]. Ann Surg Treat Res, 2021, 101(1):58-64.
43
Dozois 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 phaseⅠstem cell on matrix plug trial[J]. Dis Colon Rectum, 2023, 66(2):243-252.
44
Park KJ, Ryoo SB, Kim JS, et al. Allogeneic adipose-derived stem cells for the treatment of perianal fistula in Crohn's disease: a pilot clinical trial[J]. Colorectal Dis, 2016, 18(5):468-476.
45
Schwandner O. Stem cell injection for complex anal fistula in Crohn's disease: a single-center experience[J]. World J Gastroenterol, 2021, 27(24):3643-3653.
46
Furukawa S, Mizushima T, Nakaya R, et al. Darvadstrocel for complex perianal fistulas in Japanese adults with Crohn's disease: a phase 3 study[J]. J Crohns Colitis, 2023, 17(3):369-378.
47
Garcia-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[J]. Dis Colon Rectum, 2022, 65(5):713-720.
48
Colombo F, Cammarata F, Baldi C, et al. Stem cell injection for complex refractory perianal fistulas in Crohn's disease: a single center initial experience[J]. Front Surg, 2022, 9:834870. doi:10.3389/fsurg.2022.834870.
49
Ciccocioppo R, Bernardo ME, Sgarella A, et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease[J]. Gut, 2011, 60(6):788-798.
50
Ciccocioppo 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[J]. Mayo Clin Proc, 2015, 90(6):747-755.
51
Reenaers C, Gillard RP, Coimbra C, et al. Clinical and MRI evolution after local injection of bone marrow-derived mesenchymal stem cells in perianal fistulae in Crohn's disease: results from a prospective monocentric study[J]. J Crohns Colitis, 2023, 17(5):728-737.
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