Stem Cell Therapies for Inflammatory Bowel Disease

  • Amy L. LightnerEmail author
Inflammatory Bowel Disease (S Hanauer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Inflammatory Bowel Disease


Purpose of Review

Stem cell therapies have demonstrated safety and efficacy in the treatment of perianal Crohn’s disease as compared to conventional therapy. Thus, an understanding of their place in the treatment algorithm for inflammatory bowel disease has become imperative as we move into an era of regenerative medicine.

Recent Findings

There have now been over a dozen clinical trials highlighting stem cells as a useful therapeutic in Crohn’s disease. Due to the success in the local treatment for perianal Crohn’s disease, investigation is continuing in the space of targeted systemic delivery for the treatment of luminal disease.


As we increase the number of patients treated in clinical trials, it is imperative to define the optimal cell donor, optimize treatment dosing and retreatment protocols, and understand methods for safely targeting and treating intraluminal disease.


Mesenchymal stem cells Stem cells Luminal Crohn’s disease Perianal Crohn’s disease Regenerative medicine 


Compliance with Ethical Standards

Conflict of Interest

Amy Lightner reports working as a consultant for Takeda.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Schwartz DA, Loftus EV Jr, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, et al. The natural history of fistulizing Crohn’s disease in Olmsted County, Minnesota. Gastroenterology. 2002;122(4):875–80.CrossRefGoogle Scholar
  2. 2.
    Hannaway CD, Hull TL. Current considerations in the management of rectovaginal fistula from Crohn’s disease. Color Dis. 2008;10(8):747–55 discussion 755-746.CrossRefGoogle Scholar
  3. 3.
    Radcliffe AG, Ritchie JK, Hawley PR, Lennard-Jones JE, Northover JM. Anovaginal and rectovaginal fistulas in Crohn’s disease. Dis Colon Rectum. 1988;31(2):94–9.CrossRefGoogle Scholar
  4. 4.
    Sands BE, Blank MA, Patel K, van Deventer SJ, Study AI. Long-term treatment of rectovaginal fistulas in Crohn’s disease: response to infliximab in the ACCENT II study. Clin Gastroenterol Hepatol. 2004;2(10):912–20.CrossRefGoogle Scholar
  5. 5.
    Andreani SM, Dang HH, Grondona P, Khan AZ, Edwards DP. Rectovaginal fistula in Crohn’s disease. Dis Colon Rectum. 2007;50(12):2215–22.CrossRefGoogle Scholar
  6. 6.
    Molendijk I, Nuij VJ, van der Meulen-de Jong AE, van der Woude CJ. Disappointing durable remission rates in complex Crohn’s disease fistula. Inflamm Bowel Dis. 2014;20(11):2022–8.CrossRefGoogle Scholar
  7. 7.
    Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med. 1999;340(18):1398–405.CrossRefGoogle Scholar
  8. 8.
    Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350(9):876–85.CrossRefGoogle Scholar
  9. 9.
    Hesterberg R, Schmidt WU, Muller F, Roher HD. Treatment of anovaginal fistulas with an anocutaneous flap in patients with Crohn’s disease. Int J Color Dis. 1993;8(1):51–4.CrossRefGoogle Scholar
  10. 10.
    Hull TL, Fazio VW. Surgical approaches to low anovaginal fistula in Crohn’s disease. Am J Surg. 1997;173(2):95–8.CrossRefGoogle Scholar
  11. 11.
    Kodner IJ, Mazor A, Shemesh EI, Fry RD, Fleshman JW, Birnbaum EH. Endorectal advancement flap repair of rectovaginal and other complicated anorectal fistulas. Surgery. 1993;114(4):682–9 discussion 689-690.PubMedGoogle Scholar
  12. 12.
    Sonoda T, Hull T, Piedmonte MR, Fazio VW. Outcomes of primary repair of anorectal and rectovaginal fistulas using the endorectal advancement flap. Dis Colon Rectum. 2002;45(12):1622–8.CrossRefGoogle Scholar
  13. 13.
    Steele SR, Kumar R, Feingold DL, Rafferty JL, Buie WD, Standards Practice Task Force of the American Society of Colon and Rectal Surgeons. Practice parameters for the management of perianal abscess and fistula-in-ano. Dis Colon Rectum. 2011;54(12):1465–74.CrossRefGoogle Scholar
  14. 14.
    Wolff BG, Culp CE, Beart RW Jr, Ilstrup DM, Ready RL. Anorectal Crohn’s disease. A long-term perspective. Dis Colon Rectum. 1985;28(10):709–11.CrossRefGoogle Scholar
  15. 15.
    West RL, van der Woude CJ, Hansen BE, et al. Clinical and endosonographic effect of ciprofloxacin on the treatment of perianal fistulae in Crohn’s disease with infliximab: a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2004;20(11–12):1329–36.CrossRefGoogle Scholar
  16. 16.
    Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn disease: a meta-analysis. Ann Intern Med. 1995;123(2):132–42.CrossRefGoogle Scholar
  17. 17.
    Ford AC, Sandborn WJ, Khan KJ, Hanauer SB, Talley NJ, Moayyedi P. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106(4):644–59.CrossRefGoogle Scholar
  18. 18.
    Soltani A, Kaiser AM. Endorectal advancement flap for cryptoglandular or Crohn’s fistula-in-ano. Dis Colon Rectum. 2010;53(4):486–95.CrossRefGoogle Scholar
  19. 19.
    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. 2008;371(9624):1579–86.CrossRefGoogle Scholar
  20. 20.
    Sun L, Wang D, Liang J, Zhang H, Feng X, Wang H, et al. Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum. 2010;62(8):2467–75.CrossRefGoogle Scholar
  21. 21.
    Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. 2009;5(1):54–63.CrossRefGoogle Scholar
  22. 22.
    Yamout B, Hourani R, Salti H, Barada W, el-Hajj T, al-Kutoubi A, et al. Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study. J Neuroimmunol. 2010;227(1–2):185–9.CrossRefGoogle Scholar
  23. 23.
    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(7):1416–23.CrossRefGoogle Scholar
  24. 24.
    Gharibi T, Ahmadi M, Seyfizadeh N, Jadidi-Niaragh F, Yousefi M. Immunomodulatory characteristics of mesenchymal stem cells and their role in the treatment of multiple sclerosis. Cell Immunol. 2015;293(2):113–21.CrossRefGoogle Scholar
  25. 25.
    Kimbrel EA, Kouris NA, Yavanian GJ, Chu J, Qin Y, Chan A, et al. Mesenchymal stem cell population derived from human pluripotent stem cells displays potent immunomodulatory and therapeutic properties. Stem Cells Dev. 2014;23(14):1611–24.CrossRefGoogle Scholar
  26. 26.
    English K. Mechanisms of mesenchymal stromal cell immunomodulation. Immunol Cell Biol. 2013;91(1):19–26.CrossRefGoogle Scholar
  27. 27.
    Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ, et al. Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells. 2004;22(7):1330–7.CrossRefGoogle Scholar
  28. 28.
    Mayne CG, Williams CB. Induced and natural regulatory T cells in the development of inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(8):1772–88.CrossRefGoogle Scholar
  29. 29.
    Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6(4):345–52.CrossRefGoogle Scholar
  30. 30.
    Garcia-Olmo D, Garcia-Arranz M, Garcia LG, et al. Autologous stem cell transplantation for treatment of rectovaginal fistula in perianal Crohn’s disease: a new cell-based therapy. Int J Color Dis. 2003;18(5):451–4.CrossRefGoogle Scholar
  31. 31.
    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(2):279–85.CrossRefGoogle Scholar
  32. 32.
    Dietz AB, Dozois EJ, Fletcher JG, Butler GW, Radel D, Lightner AL, et al. Autologous mesenchymal stem cells, applied in a bioabsorbable matrix, for treatment of perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2017;153(1):59–62 e52.CrossRefGoogle Scholar
  33. 33.
    Garcia-Olmo D, Herreros D, Pascual I, Pascual JA, del-Valle E, Zorrilla J, 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.CrossRefGoogle Scholar
  34. 34.
    Molendijk I, Bonsing BA, Roelofs H, Peeters KCMJ, Wasser MNJM, Dijkstra G, 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 e916.CrossRefGoogle Scholar
  35. 35.
    Cho YB, Park KJ, Yoon SN, Song KH, Kim DS, Jung SH, 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):532–7.CrossRefGoogle Scholar
  36. 36.
    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 Color Dis. 2013;28(3):313–23.CrossRefGoogle Scholar
  37. 37.
    • 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. 2016;388(10051):1281–90 First phase III trial utilizing MSCs for the treament of perianal Crohn’s disease which showed that the treatment arm had improved healing compared to the control. CrossRefGoogle Scholar
  38. 38.
    Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, et al. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut. 2011;60(6):788–98.CrossRefGoogle Scholar
  39. 39.
    Lee WY, Park KJ, Cho YB, Yoon SN, Song KH, Kim DS, et al. Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn’s fistula. Stem Cells. 2013;31(11):2575–81.CrossRefGoogle Scholar
  40. 40.
    Lo Surdo JL, Millis BA, Bauer SR. Automated microscopy as a quantitative method to measure differences in adipogenic differentiation in preparations of human mesenchymal stromal cells. Cytotherapy. 2013;15(12):1527–40.CrossRefGoogle Scholar
  41. 41.
    Sammour I, Somashekar S, Huang J, Batlahally S, Breton M, Valasaki K, et al. The effect of gender on mesenchymal stem cell (MSC) efficacy in neonatal hyperoxia-induced lung injury. PLoS One. 2016;11(10):e0164269.CrossRefGoogle Scholar
  42. 42.
    Serena C, Keiran N, Madeira A, Maymó-Masip E, Ejarque M, Terrón-Puig M, et al. Crohn’s disease disturbs the immune properties of human adipose-derived stem cells related to inflammasome activation. Stem Cell Rep. 2017;9(4):1109–23.CrossRefGoogle Scholar
  43. 43.
    Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32(3):252–60.CrossRefGoogle Scholar
  44. 44.
    Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, 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(22):2369–79.CrossRefGoogle Scholar
  45. 45.
    Pezzanite LM, Fortier LA, Antczak DF, Cassano JM, Brosnahan MM, Miller D, et al. Equine allogeneic bone marrow-derived mesenchymal stromal cells elicit antibody responses in vivo. Stem Cell Res Ther. 2015;6:54.CrossRefGoogle Scholar
  46. 46.
    Trounson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell. 2015;17(1):11–22.CrossRefGoogle Scholar
  47. 47.
    Brandt LJ, Bernstein LH, Boley SJ, Frank MS. Metronidazole therapy for perineal Crohn’s disease: a follow-up study. Gastroenterology. 1982;83(2):383–7.PubMedGoogle Scholar
  48. 48.
    Goldstein ES, Marion JF, Present DH. 6-Mercaptopurine is effective in Crohn’s disease without concomitant steroids. Inflamm Bowel Dis. 2004;10(2):79–84.CrossRefGoogle Scholar
  49. 49.
    Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med. 1995;123(2):132–42.CrossRefGoogle Scholar
  50. 50.
    •• Panes J, Garcia-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 e1334 Reported one year outcomes of the first phase III trials utilizing MSCs for the treatment of perinal Crohn’s disease, demonstrating the lasting effects of using cellular therapy. CrossRefGoogle Scholar
  51. 51.
    Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009;18(5):683–92.CrossRefGoogle Scholar
  52. 52.
    Zhang J, Lv S, Liu X, Song B, Shi L. Umbilical cord mesenchymal stem cell treatment for Crohn’s disease: a randomized controlled clinical trial. Gut Liver. 2018;12(1):73–8.CrossRefGoogle Scholar
  53. 53.
    •• 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(1):64–71 A phase II study which shows systemic delivery of MSCs may prove effective for the treatment of medically refractory Crohn’s luminal disease. THere were no adverse events related to the MSCs themselves. CrossRefGoogle Scholar
  54. 54.
    Hessel SJ, Adams DF, Abrams HL. Complications of angiography. Radiology. 1981;138(2):273–81.CrossRefGoogle Scholar
  55. 55.
    Dinesen M, Lundmark M, Albrechtsen M. Complete genome sequences of two isolates of Kalanchoe latent virus. Arch Virol. 2009;154(7):1173–5.CrossRefGoogle Scholar
  56. 56.
    Hu J, Zhao G, Zhang L, Qiao C, di A, Gao H, et al. Safety and therapeutic effect of mesenchymal stem cell infusion on moderate to severe ulcerative colitis. Exp Ther Med. 2016;12(5):2983–9.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Colon and Rectal SurgeryCleveland ClinicClevelandUSA

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