Digestive Diseases and Sciences

, Volume 62, Issue 4, pp 851–860 | Cite as

Efficacy of Mesenchymal Stromal Cells for Fistula Treatment of Crohn’s Disease: A Systematic Review and Meta-Analysis

  • Yantian Cao
  • Zhen Ding
  • Chaoqun Han
  • Huiying Shi
  • Lianlian Cui
  • Rong LinEmail author


Background and Aim

The introduction of mesenchymal stromal cells (MSCs) has changed the management of Crohn’s fistula, while it remains controversial. The aim of this study was to provide an overview of efficacy and optimum state of MSCs treatment on Crohn’s fistula.


Studies reporting MSCs treatment on Crohn’s fistula were searched and included. A fixed-effects model was used to assess the efficacy of MSCs, and outcomes of healing and recurrence were used to evaluate the best states of MSCs intervention.


Fourteen articles were enrolled (n = 477). Pooled analysis showed MSCs had a significant efficacy compared to other treatments [risk difference: 0.21 (0.09, 0.32), P = 0.000]. Notably, after MSCs treatment, the group of Crohn’s disease activity index (CDAI) baseline >150 group had a higher healing rate (HR) and a clinical response (a change in CDAI of >50 points) (79.17 ± 8.78 vs. 47.54 ± 15.90, P = 0.011) compared to CDAI baseline of <150. The duration time of CD and fistulas had a negative correlation with HR accompanied by MSC therapy (r = −0.900, −0.925). Then, a moderate dose MSCs (2–4 × 107 cells/ml) had a higher HR (80.07%) and lower recurrence rate (RR 13.98%) compared to other dosages. Moreover, adipose-derived MSCs therapy had an advantage over bone marrow-derived MSCs in terms of low RR (7.4 ± 4.28 vs. 13.39 ± 0.89).


The evidence supported the effect of MSCs at a more appropriate time of Crohn’s fistula. And CDAI baseline (the points >150) has been a candidate for evaluating effectiveness of MSCs application on Crohn’s fistula.


Mesenchymal stromal cells (MSCs) Adipose-derived mesenchymal stem cells (ASCs) Crohn’s fistula Healing rate (HR) Recurrence rate (RR) 



This study was supported in part by the National Natural Science Foundation of China (Nos. 81272656, 81572428, 81330014).

Compliance with ethical standards

Conflicts of interest



  1. 1.
    American Gastroenterological Association medical position statement. perianal Crohn’s disease. Gastroenterology. 2003;125:1503–1507.CrossRefGoogle Scholar
  2. 2.
    Ardizzone S, Porro GB. Perianal Crohn’s disease: overview. Dig Liver Dis. 2007;39:957–958.CrossRefPubMedGoogle Scholar
  3. 3.
    Peloquin JM, Goel G, Villablanca EJ, Xavier RJ. Mechanisms of pediatric inflammatory bowel disease. Annu Rev Immunol. 2016;34:31–64.CrossRefPubMedGoogle Scholar
  4. 4.
    Bansal P, Sonnenberg A. Risk factors of colorectal cancer in inflammatory bowel disease. Am J Gastroenterol. 1996;91:44–48.PubMedGoogle Scholar
  5. 5.
    Jess T, Gamborg M, Matzen P, Munkholm P, Sorensen TI. Increased risk of intestinal cancer in Crohn’s disease: a meta-analysis of population-based cohort studies. Am J Gastroenterol. 2005;100:2724–2729.CrossRefPubMedGoogle Scholar
  6. 6.
    Canavan C, Abrams KR, Mayberry J. Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn’s disease. Aliment Pharmacol Ther. 2006;23:1097–1104.CrossRefPubMedGoogle Scholar
  7. 7.
    von Roon AC, Reese G, Teare J, Constantinides V, Darzi AW, Tekkis PP. The risk of cancer in patients with Crohn’s disease. Dis Colon Rectum. 2007;50:839–855.CrossRefGoogle Scholar
  8. 8.
    Algaba A, Guerra I, Castano A, et al. Risk of cancer, with special reference to extra-intestinal malignancies, in patients with inflammatory bowel disease. World J Gastroenterol. 2013;19:9359–9365.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Beaugerie L, Sokol H, Seksik P. Noncolorectal malignancies in inflammatory bowel disease: more than meets the eye. Dig Dis (Basel, Switzerland). 2009;27:375–381.CrossRefGoogle Scholar
  10. 10.
    Katsanos KH, Tatsioni A, Pedersen N, et al. Cancer in inflammatory bowel disease 15 years after diagnosis in a population-based European collaborative follow-up study. J Crohn’s Colitis. 2011;5:430–442.CrossRefGoogle Scholar
  11. 11.
    Pedersen N, Duricova D, Elkjaer M, Gamborg M, Munkholm P, Jess T. Risk of extra-intestinal cancer in inflammatory bowel disease: meta-analysis of population-based cohort studies. Am J Gastroenterol. 2010;105:1480–1487.CrossRefPubMedGoogle Scholar
  12. 12.
    Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–444.CrossRefPubMedGoogle Scholar
  13. 13.
    Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet (London, England). 2008;371:1579–1586.CrossRefGoogle Scholar
  14. 14.
    Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815–1822.CrossRefPubMedGoogle Scholar
  15. 15.
    Alvaro-Gracia JM, Jover JA, Garcia-Vicuna R, et al. Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial. Ann Rheum Dis. 2016.Google Scholar
  16. 16.
    Jauregui-Amezaga A, Rovira M, Marin P, et al. Improving safety of autologous haematopoietic stem cell transplantation in patients with Crohn’s disease. Gut. 2016;65:1456–1462.CrossRefPubMedGoogle Scholar
  17. 17.
    Lin R, Ding Z, Ma H, et al. In vitro conditioned bone marrow-derived mesenchymal stem cells promote de novo functional enteric nerve regeneration, but not through direct-transdifferentiation. Stem Cells (Dayton, Ohio). 2015;33:3545–3557.CrossRefGoogle Scholar
  18. 18.
    Lin R, Ma H, Ding Z, et al. Bone marrow-derived mesenchymal stem cells favor the immunosuppressive T cells skewing in a Helicobacter pylori model of gastric cancer. Stem Cells Dev. 2013;22:2836–2848.CrossRefPubMedGoogle Scholar
  19. 19.
    Duijvestein M, Vos AC, Roelofs H, et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut. 2010;59:1662–1669.CrossRefPubMedGoogle Scholar
  20. 20.
    Garcia-Olmo D, Garcia-Arranz M, Herreros D, Pascual I, Peiro C, Rodriguez-Montes JA. A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005;48:1416–1423.CrossRefPubMedGoogle Scholar
  21. 21.
    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;149:918.e916–927.e916.CrossRefGoogle Scholar
  22. 22.
    Garcia-Olmo D, Garcia-Arranz M, Herreros D. Expanded adipose-derived stem cells for the treatment of complex perianal fistula including Crohn’s disease. Exp Opin Biol Ther. 2008;8:1417–1423.CrossRefGoogle Scholar
  23. 23.
    Sanz-Baro R, Garcia-Arranz M, Guadalajara H, de la Quintana P, Herreros MD, Garcia-Olmo D. First-in-human case study: pregnancy in women with Crohn’s perianal fistula treated with adipose-derived stem cells: a safety study. Stem Cells Transl Med. 2015;4:598–602.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ciccocioppo R, Gallia A, Sgarella A, Kruzliak P, Gobbi PG, Corazza GR. Long-term follow-up of CD fistulas after local injections of bone marrow-derived mesenchymal stem cells. Mayo Clin Proc. 2015;90:747–755.CrossRefPubMedGoogle Scholar
  25. 25.
    de la Portilla F, Alba F, Garcia-Olmo D, Herrerias JM, Gonzalez FX, Galindo A. 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;28:313–323.CrossRefPubMedGoogle Scholar
  26. 26.
    Georgakis MK, Thomopoulos TP, Diamantaras AA, et al. Association of age at menopause and duration of reproductive period with depression after menopause: a systematic review and meta-analysis. JAMA Psychiatry. 2016;73:139–149.CrossRefPubMedGoogle Scholar
  27. 27.
    Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006;63:530–538.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ (Clinical Research ed). 2003;327:557–560.CrossRefGoogle Scholar
  29. 29.
    Forbes GM, Sturm MJ, Leong RW, et al. A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn’s disease refractory to biologic therapy. Clin Gastroenterol Hepatol. 2014;12:64–71.CrossRefPubMedGoogle Scholar
  30. 30.
    Knyazev OV, Parfenov AI, Shcherbakov PL, Ruchkina IN, Konoplyannikov AG. Cell therapy of refractory Crohn’s disease. Bull Exp Biol Med. 2013;156:139–145.CrossRefPubMedGoogle Scholar
  31. 31.
    Garcia-Arranz M, Dolores Herreros M, Gonzalez-Gomez 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 Trans Med. 2016.Google Scholar
  32. 32.
    Garcia-Olmo D, Guadalajara H, Rubio-Perez I, Herreros MD, de-la-Quintana P, Garcia-Arranz M. Recurrent anal fistulae: limited surgery supported by stem cells. World J Gastroenterol. 2015;21:3330–3336.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Guadalajara H, Herreros D, De-La-Quintana P, Trebol J, Garcia-Arranz M, Garcia-Olmo D. Long-term follow-up of patients undergoing adipose-derived adult stem cell administration to treat complex perianal fistulas. Int J Colorectal Dis. 2012;27:595–600.CrossRefPubMedGoogle Scholar
  34. 34.
    Mizushima T, Takahashi H, Takeyama H, et al. A clinical trial of autologous adipose-derived regenerative cell transplantation for a postoperative enterocutaneous fistula. Surg Today. 2016;46:835–842.CrossRefPubMedGoogle Scholar
  35. 35.
    Ciccocioppo R, Bernardo ME, Sgarella A, et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut. 2011;60:788–798.CrossRefPubMedGoogle Scholar
  36. 36.
    Cho YB, Park KJ, Yoon SN, Song KH, et al. Long-term results of adipose-derived stem cell therapy for the treatment of Crohn’s fistula. Stem Cells Transl Med. 2015;4:532–537.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lee WY, Park KJ, Cho YB, Yoon SN, Song KH, et al. Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn’s fistula. Stem Cells (Dayton, Ohio). 2013;31:2575–2581.CrossRefGoogle Scholar
  38. 38.
    Cho YB, Lee WY, Park KJ, Kim M, Yoo HW, Yu CS. Autologous adipose tissue-derived stem cells for the treatment of Crohn’s fistula: a phase I clinical study. Cell Transplant. 2013;22:279–285.CrossRefPubMedGoogle Scholar
  39. 39.
    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;52:79–86.CrossRefPubMedGoogle Scholar
  40. 40.
    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. Colorectal Dis. 2016;18:468–476.CrossRefPubMedGoogle Scholar
  41. 41.
    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. Lancet (London, England). 2016;388:1281–1290.CrossRefGoogle Scholar
  42. 42.
    Garcia-Olmo D, Herreros D, Pascual M, et al. Treatment of enterocutaneous fistula in Crohn’s disease with adipose-derived stem cells: a comparison of protocols with and without cell expansion. Int J Colorectal Dis. 2009;24:27–30.CrossRefPubMedGoogle Scholar
  43. 43.
    Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350:876–885.CrossRefPubMedGoogle Scholar
  44. 44.
    Levy C, Tremaine WJ. Management of internal fistulas in Crohn’s disease. Inflamm Bowel Dis. 2002;8:106–111.CrossRefPubMedGoogle Scholar
  45. 45.
    Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in CD. A meta-analysis. Ann Intern Med. 1995;123:132–142.CrossRefPubMedGoogle Scholar
  46. 46.
    Hermann J, Eder P, Banasiewicz T, Matysiak K, Lykowska-Szuber L. Current management of anal fistulas in Crohn’s disease. Prz Gastroenterol. 2015;10:83–88.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Akiba RT, Rodrigues FG, da Silva G. Management of complex perineal fistula disease. Clin Colon Rectal Surg. 2016;29:92–100.CrossRefPubMedGoogle Scholar
  48. 48.
    Gecse KB, Bemelman W, Kamm MA, et al. A global consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn’s disease. Gut. 2014;63:1381–1392.CrossRefPubMedGoogle Scholar
  49. 49.
    Ritchie RD, Sackier JM, Hodde JP. Incontinence rates after cutting seton treatment for anal fistula. Colorectal Dis. 2009;11:564–571.CrossRefPubMedGoogle Scholar
  50. 50.
    van Koperen PJ, Safiruddin F, Bemelman WA, Slors JF. Outcome of surgical treatment for fistula in ano in Crohn’s disease. Br J Surg. 2009;96:675–679.CrossRefPubMedGoogle Scholar
  51. 51.
    Present DH. Crohn’s fistula: current concepts in management. Gastroenterology. 2003;124:1629–1635.CrossRefPubMedGoogle Scholar
  52. 52.
    Khanna R, Zou G, D’Haens G, et al. A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn’s disease activity. Aliment Pharmacol Ther. 2015;41:77–86.CrossRefPubMedGoogle Scholar
  53. 53.
    Best WR, Becktel JM, Singleton JW. Rederived values of the eight coefficients of the Crohn’s Disease Activity Index (CDAI). Gastroenterology. 1979;77:843–846.PubMedGoogle Scholar
  54. 54.
    Peyrin-Biroulet L, Reinisch W, Colombel JF, et al. Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn’s disease in the SONIC trial. Gut. 2014;63:88–95.CrossRefPubMedGoogle Scholar
  55. 55.
    Hamamoto H, Gorman JH, Ryan LP, et al. Allogeneic mesenchymal precursor cell therapy to limit remodeling after myocardial infarction: the effect of cell dosage. Ann Thorac Surg. 2009;87:794–801.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Hare JM, Fishman JE, Gerstenblith G, et al. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA. 2012;308:2369–2379.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Hoogduijn MJ, Betjes MG, Baan CC. Mesenchymal stromal cells for organ transplantation: different sources and unique characteristics? Curr Opin Organ Transpl. 2008;19:41–46.CrossRefGoogle Scholar
  58. 58.
    Xie M, Qin H, Luo Q, et al. Comparison of adipose-derived and bone marrow mesenchymal stromal cells in a murine model of Crohn’s disease. Dig Dis Sci. 2017;62:115–123.CrossRefPubMedGoogle Scholar
  59. 59.
    Melief SM, Schrama E, Brugman MH, et al. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages. Stem Cells. 2013;31:1980–1991.CrossRefPubMedGoogle Scholar
  60. 60.
    Lalu MM, McIntyre L, Pugliese C, et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7:e47559.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Yantian Cao
    • 1
  • Zhen Ding
    • 1
  • Chaoqun Han
    • 1
  • Huiying Shi
    • 1
  • Lianlian Cui
    • 1
  • Rong Lin
    • 1
    Email author
  1. 1.Division of Gastroenterology, Union Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

Personalised recommendations