Progress of stem cell transplantation for treating complex anal fistula_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WEI Xiaoling ¹ , ZHANG Zhiqian ² ,  GENG Xuesi ²

1. Fujian University of Traditional Chinese Medicine, Fuzhou 350108, P. R. China;
2. Department of Anorectal Surgery, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian 361009, P. R. China;

Corresponding author：

GENG Xuesi, Email: 786049508@qq.com

Keywords：

stem cell; complex anal fistula; Crohn’s disease; treatment

DOI：

10.7507/1007-9424.201903109

Video：

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Objective To understand progress of stem cell transplantation in treatment of complex anal fistula.Method The relevant literatures were searched in the PubMed, Web of Science, CNKI, Wanfang, and other databases and the clinical efficacy, advantages and problems of the therapy were analyzed and summarized.Results The stem cells currently used in the field of complex anal fistula were mainly the adipose tissue-derived stem cells, which had the biological characteristics of regenerative differentiation, immune regulation, and repair of intestinal mucosal barrier, which could be used as the seed cells for the treatment of complex anal fistula, its effectiveness was worthy of recognition. But its long-term clinical efficacy remained to be seen due to its clinical treatment options were different and lack of uniform standards. The safety of treatment for complex anal fistula was payed a attention because the stem cells had the oncogene activation and tumor suppressor gene inactivation characteristics.Conclusions Stem cell transplantation, as an emerging therapy, has broad prospects for patients with complex anal fistula that are difficult to solve by surgery, but its long-term efficacy is still unsatisfactory. Due to current sample size, short observation time, and lack of randomized control, current clinical data is not convincing, and high cost also limits its development of technology.

Citation： WEI Xiaoling, ZHANG Zhiqian, GENG Xuesi. Progress of stem cell transplantation for treating complex anal fistula. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2019, 26(7): 887-891. doi: 10.7507/1007-9424.201903109 Copy

1.	Steele SR, Kumar R, Feingold DL, et al. Practice parameters for the management of perianal abscess and fistula-in-ano. Dis Colon Rectum, 2011, 54(12): 1465-1474.
2.	Vogel JD, Johnson EK, Morris AM, et al. Clinical practice guideline for the management of anorectal abscess, fistula-in-ano, and rectovaginal fistula. Dis Colon Rectum, 2016, 59(12): 1117-1133.
3.	Göttgens KW, Smeets RR, Stassen LP, et al. Systematic review and meta-analysis of surgical interventions for high cryptoglandular perianal fistula. Int J Colorectal Dis, 2015, 30(5): 583-593.
4.	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. Gastroenterology, 2015, 149(4): 918-927.
5.	Garcia-Olmo D, Schwartz DA. Cumulative evidence that mesenchymal stem cells promote healing of perianal fistulas of patients with Crohn’s disease—going from bench to bedside. Gastroenterology, 2015, 149(4): 853-857.
6.	李森娟, 沈桂鑫, 邱敏, 等. 干细胞移植治疗复杂性肛瘘疗效的Meta分析. 浙江医学, 2018, 40(3): 262-265.
7.	Clerici M, Cassinotti A, Onida F, et al. Immunomodulatory effects of unselected haematopoietic stem cells autotransplantation in refractory Crohn’s disease. Dig Liver Dis, 2011, 43(12): 946-952.
8.	Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol, 2012, 12(5): 383-396.
9.	Lightner 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.
10.	Deng X, Szabo S, Chen L, et al. New cell therapy using bone marrow-derived stem cells/endothelial progenitor cells to accelerate neovascularization in healing of experimental ulcerative colitis. Curr Pharm Des, 2011, 17(16): 1643-1651.
11.	Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng, 2001, 7(2): 211-228.
12.	刘琴, 王丽平, 陈芳, 等. 脂肪干细胞分离研究进展. 华南国防医学杂志, 2018, 32(4): 281-285.
13.	Debnath T, Ghosh S, Potlapuvu US, et al. Proliferation and differentiation potential of human adipose-derived stem cells grown on chitosan hydrogel. PLoS One, 2015, 10(3): e0120803.
14.	李玉秋, 张雷雷, 黄飞. 人脂肪干细胞的分离、培养及鉴定. 沈阳医学院学报, 2018, 20(6): 495-498.
15.	Taxonera C, Schwartz DA, García-Olmo D. Emerging treatments for complex perianal fistula in Crohn’s disease. World J Gastroenterol, 2009, 15(34): 4263-4272.
16.	Ratajczak MZ. Stem cells and mechanisms regulating their trafficking—a new and challenging area of investigation in modern psychiatry. Prog Neuropsychopharmacol Biol Psychiatry, 2018, 80(Pt A): 1-2.
17.	魏兆明, 江文胜, 高艺, 等. 脂肪间充质干细胞的生物学特性及潜在临床应用. 中国临床药理学与治疗学, 2019, 24(1): 116-120.
18.	杨芳, 陈书强, 芦洁董, 等. 人脂肪干细胞膜片的构建及其生物学特性初探. 解放军医学院学报, 2018, 39(2): 144-149.
19.	Ma S, Xie N, Li W, et al. Immunobiology of mesenchymal stem cells. Cell Death Differ, 2014, 21(2): 216-225.
20.	郭蕊, 薛春雨. 脂肪干细胞的免疫调节作用及临床应用. 第二军医大学学报, 2018, 39(12): 1370-1374.
21.	晏贤慧, 张培华. 脂肪干细胞在创伤修复中的研究进展. 海南医学, 2018, 29(12): 1726-1729.
22.	Garcia-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.
23.	Herreros 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.
24.	Kim YS, Choi YJ, Suh DS, et al. Mesenchymal stem cell implantation in osteoarthritic knees: is fibrin glue effective as a scaffold? . Am J Sports Med, 2015, 43(1): 176-185.
25.	刘艳妮, 倪敏, 张睿, 等. 脂肪干细胞治疗复杂性肛瘘: 作用与机制. 中国组织工程研究, 2018, 22(33): 5399-5407.
26.	Lobascio P, Balducci G, Minafra M, et al. Adipose-derived stem cells (MYSTEM® EVO Technology) as a treatment for complex transsphincteric anal fistula. Tech Coloproctol, 2018, 22(5): 373-377.
27.	García-Olmo D, García-Arranz M, García LG, et al. Autologous stem cell transplantation for treatment of rectovaginal fistula in perianal Crohn’s disease: a new cell-based therapy. Int J Colorectal Dis, 2003, 18(5): 451-454.
28.	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.
29.	Piejko M, Romaniszyn M, Borowczyk-Micha? owska J, et al. Cell therapy in surgical treatment of fistulas. Preliminary results. Pol Przegl Chir, 2017, 89(3): 48-51.
30.	de la Portilla F, Alba F, García-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/Ⅱa clinical trial. Int J Colorectal Dis, 2013, 28(3): 313-323.
31.	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. Stem Cells, 2013, 31(11): 2575-2581.
32.	Wainstein C, Quera R, Fluxá D, et al. Stem cell therapy in refractory perineal Crohn’s disease: long-term follow-up. Colorectal Dis, 2018: 6.
33.	Bruno S, Deregibus MC, Camussi G. The secretome of mesenchymal stromal cells: Role of extracellular vesicles in immunomodulation. Immunol Lett, 2015, 168(2): 154-158.
34.	Narang SK, Keogh K, Alam NN, et al. A systematic review of new treatments for cryptoglandular fistula in ano. Surgeon, 2017, 15(1): 30-39.
35.	Panes J, Garcia-Olmo D, Van Assche D, et al. A phase Ⅲ randomised controlled trial of Cx601, expanded allogeneic adipose-derived mesenchymal stem cells (eASC), for complex perianal fistulas in Crohn’s disease. J Crohns Colitis, 2016, 10(Suppl1): S1.
36.	Ryska O, Serclova Z, Mestak O, et al. Local application of adipose-derived mesenchymal stem cells supports the healing of fistula: prospective randomised study on rat model of fistulising Crohn’s disease. Scand J Gastroenterol, 2017, 52(5): 543-550.
37.	Choi S, Ryoo SB, Park KJ, et al. Autologous adipose tissue-derived stem cells for the treatment of complex perianal fistulas not associated with Crohn’s disease: a phase Ⅱ clinical trial for safety and efficacy. Tech Coloproctol, 2017, 21(5): 345-353.
38.	邵俊峰. 间充质干细胞与肿瘤关系的研究进展. 蚌埠医学院学报, 2019, 44(1): 134-137.
39.	Tang RJ, Shen SN, Zhao XY, et al. Mesenchymal stem cells-regulated Treg cells suppress colitis-associated colorectal cancer. Stem Cell Res Ther, 2015, 6: 71.
40.	Mannon PJ. Remestemcel-L: human mesenchymal stem cells as an emerging therapy for Crohn’s disease. Expert Opin Biol Ther, 2011, 11(9): 1249-1256.

1. Steele SR, Kumar R, Feingold DL, et al. Practice parameters for the management of perianal abscess and fistula-in-ano. Dis Colon Rectum, 2011, 54(12): 1465-1474.
2. Vogel JD, Johnson EK, Morris AM, et al. Clinical practice guideline for the management of anorectal abscess, fistula-in-ano, and rectovaginal fistula. Dis Colon Rectum, 2016, 59(12): 1117-1133.
3. Göttgens KW, Smeets RR, Stassen LP, et al. Systematic review and meta-analysis of surgical interventions for high cryptoglandular perianal fistula. Int J Colorectal Dis, 2015, 30(5): 583-593.
4. 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. Gastroenterology, 2015, 149(4): 918-927.
5. Garcia-Olmo D, Schwartz DA. Cumulative evidence that mesenchymal stem cells promote healing of perianal fistulas of patients with Crohn’s disease—going from bench to bedside. Gastroenterology, 2015, 149(4): 853-857.
6. 李森娟, 沈桂鑫, 邱敏, 等. 干细胞移植治疗复杂性肛瘘疗效的Meta分析. 浙江医学, 2018, 40(3): 262-265.
7. Clerici M, Cassinotti A, Onida F, et al. Immunomodulatory effects of unselected haematopoietic stem cells autotransplantation in refractory Crohn’s disease. Dig Liver Dis, 2011, 43(12): 946-952.
8. Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol, 2012, 12(5): 383-396.
9. Lightner 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.
10. Deng X, Szabo S, Chen L, et al. New cell therapy using bone marrow-derived stem cells/endothelial progenitor cells to accelerate neovascularization in healing of experimental ulcerative colitis. Curr Pharm Des, 2011, 17(16): 1643-1651.
11. Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng, 2001, 7(2): 211-228.
12. 刘琴, 王丽平, 陈芳, 等. 脂肪干细胞分离研究进展. 华南国防医学杂志, 2018, 32(4): 281-285.
13. Debnath T, Ghosh S, Potlapuvu US, et al. Proliferation and differentiation potential of human adipose-derived stem cells grown on chitosan hydrogel. PLoS One, 2015, 10(3): e0120803.
14. 李玉秋, 张雷雷, 黄飞. 人脂肪干细胞的分离、培养及鉴定. 沈阳医学院学报, 2018, 20(6): 495-498.
15. Taxonera C, Schwartz DA, García-Olmo D. Emerging treatments for complex perianal fistula in Crohn’s disease. World J Gastroenterol, 2009, 15(34): 4263-4272.
16. Ratajczak MZ. Stem cells and mechanisms regulating their trafficking—a new and challenging area of investigation in modern psychiatry. Prog Neuropsychopharmacol Biol Psychiatry, 2018, 80(Pt A): 1-2.
17. 魏兆明, 江文胜, 高艺, 等. 脂肪间充质干细胞的生物学特性及潜在临床应用. 中国临床药理学与治疗学, 2019, 24(1): 116-120.
18. 杨芳, 陈书强, 芦洁董, 等. 人脂肪干细胞膜片的构建及其生物学特性初探. 解放军医学院学报, 2018, 39(2): 144-149.
19. Ma S, Xie N, Li W, et al. Immunobiology of mesenchymal stem cells. Cell Death Differ, 2014, 21(2): 216-225.
20. 郭蕊, 薛春雨. 脂肪干细胞的免疫调节作用及临床应用. 第二军医大学学报, 2018, 39(12): 1370-1374.
21. 晏贤慧, 张培华. 脂肪干细胞在创伤修复中的研究进展. 海南医学, 2018, 29(12): 1726-1729.
22. Garcia-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.
23. Herreros 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.
24. Kim YS, Choi YJ, Suh DS, et al. Mesenchymal stem cell implantation in osteoarthritic knees: is fibrin glue effective as a scaffold? . Am J Sports Med, 2015, 43(1): 176-185.
25. 刘艳妮, 倪敏, 张睿, 等. 脂肪干细胞治疗复杂性肛瘘: 作用与机制. 中国组织工程研究, 2018, 22(33): 5399-5407.
26. Lobascio P, Balducci G, Minafra M, et al. Adipose-derived stem cells (MYSTEM® EVO Technology) as a treatment for complex transsphincteric anal fistula. Tech Coloproctol, 2018, 22(5): 373-377.
27. García-Olmo D, García-Arranz M, García LG, et al. Autologous stem cell transplantation for treatment of rectovaginal fistula in perianal Crohn’s disease: a new cell-based therapy. Int J Colorectal Dis, 2003, 18(5): 451-454.
28. 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.
29. Piejko M, Romaniszyn M, Borowczyk-Micha? owska J, et al. Cell therapy in surgical treatment of fistulas. Preliminary results. Pol Przegl Chir, 2017, 89(3): 48-51.
30. de la Portilla F, Alba F, García-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/Ⅱa clinical trial. Int J Colorectal Dis, 2013, 28(3): 313-323.
31. 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. Stem Cells, 2013, 31(11): 2575-2581.
32. Wainstein C, Quera R, Fluxá D, et al. Stem cell therapy in refractory perineal Crohn’s disease: long-term follow-up. Colorectal Dis, 2018: 6.
33. Bruno S, Deregibus MC, Camussi G. The secretome of mesenchymal stromal cells: Role of extracellular vesicles in immunomodulation. Immunol Lett, 2015, 168(2): 154-158.
34. Narang SK, Keogh K, Alam NN, et al. A systematic review of new treatments for cryptoglandular fistula in ano. Surgeon, 2017, 15(1): 30-39.
35. Panes J, Garcia-Olmo D, Van Assche D, et al. A phase Ⅲ randomised controlled trial of Cx601, expanded allogeneic adipose-derived mesenchymal stem cells (eASC), for complex perianal fistulas in Crohn’s disease. J Crohns Colitis, 2016, 10(Suppl1): S1.
36. Ryska O, Serclova Z, Mestak O, et al. Local application of adipose-derived mesenchymal stem cells supports the healing of fistula: prospective randomised study on rat model of fistulising Crohn’s disease. Scand J Gastroenterol, 2017, 52(5): 543-550.
37. Choi S, Ryoo SB, Park KJ, et al. Autologous adipose tissue-derived stem cells for the treatment of complex perianal fistulas not associated with Crohn’s disease: a phase Ⅱ clinical trial for safety and efficacy. Tech Coloproctol, 2017, 21(5): 345-353.
38. 邵俊峰. 间充质干细胞与肿瘤关系的研究进展. 蚌埠医学院学报, 2019, 44(1): 134-137.
39. Tang RJ, Shen SN, Zhao XY, et al. Mesenchymal stem cells-regulated Treg cells suppress colitis-associated colorectal cancer. Stem Cell Res Ther, 2015, 6: 71.
40. Mannon PJ. Remestemcel-L: human mesenchymal stem cells as an emerging therapy for Crohn’s disease. Expert Opin Biol Ther, 2011, 11(9): 1249-1256.

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Progress of stem cell transplantation for treating complex anal fistula

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