Advertisement

Stem Cells in Inflammatory Bowel Disease: From Pathogenesis to Clinical Practice

  • Christos Zavos
Chapter
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

Despite the advances in the pharmacological treatment with the introduction to the market of new biological agents, a significant proportion of patients with inflammatory bowel disease (IBD) still suffer an aggressive disease course. Moreover, surgery is not always a viable option due to the location or extent of the disease, particularly in complicated Crohn’s disease patients (e.g., in the presence of fistulas). Lately, stem cell (SC)-based therapy, mainly comprising hematopoietic SCs (HSCs) and mesenchymal SCs (MSCs), has been proposed as an alternative approach to biological agents for IBD treatment. The rapid advances that occurred in MSC research, known to exhibit regenerative, paracrine, and immunoregulatory properties, have raised hope for their therapeutic potential in IBD, especially after the recent official approval of darvadstrocel, the first allogeneic MSC therapy in Europe. In this chapter, the pathophysiology of gastrointestinal SCs and all the latest literature concerning their use in IBD treatment are discussed, mainly focusing on the latest clinical trials in IBD patients. Finally, safety of HSC- and MSC-based therapies are discussed, and insight is provided for the questions needed to be answered by future studies.

Keywords

Stem cells Inflammatory bowel disease Crohn’s disease Ulcerative colitis 

References

  1. 1.
    Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol. 2007;5:1424–9.CrossRefGoogle Scholar
  2. 2.
    Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2018;390:2769–78.CrossRefGoogle Scholar
  3. 3.
    Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54.e42.CrossRefGoogle Scholar
  4. 4.
    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. Gastroenterology. 2013;145:158–65.e2.CrossRefGoogle Scholar
  5. 5.
    Fiocchi C. IBD: advances in pathogenesis, complications, diagnosis, and therapy. Curr Opin Gastroenterol. 2012;28:297–300.CrossRefGoogle Scholar
  6. 6.
    Sandborn WJ. Current directions in IBD therapy: what goals are feasible with biological modifiers? Gastroenterology. 2008;135:1442–7.CrossRefGoogle Scholar
  7. 7.
    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;60:788–98.CrossRefGoogle Scholar
  8. 8.
    van Deen WK, Oikonomopoulos A, Hommes DW. Stem cell therapy in inflammatory bowel disease: which, when and how? Curr Opin Gastroenterol. 2013;29:384–90.CrossRefGoogle Scholar
  9. 9.
    Lanzoni G, Roda G, Belluzzi A, et al. Inflammatory bowel disease: moving toward a stem cell-based therapy. World J Gastroenterol. 2008;14:4616–26.CrossRefGoogle Scholar
  10. 10.
    Pilpilidis I, Kountouras J, Zavos C, Katsinelos P. Upper gastrointestinal carcinogenesis: H. pylori and stem cell cross-talk. J Surg Res. 2011;166:255–64.CrossRefGoogle Scholar
  11. 11.
    Singh UP, Singh NP, Singh B, et al. Stem cells as potential therapeutic targets for inflammatory bowel disease. Front Biosci (Schol Ed). 2010;2:993–1008.CrossRefGoogle Scholar
  12. 12.
    van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol. 2009;71:241–60.CrossRefGoogle Scholar
  13. 13.
    Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007;25:2739–49.CrossRefGoogle Scholar
  14. 14.
    Friedenstein AJ, Chailakhyan RK, Latsinik NV, et al. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation. 1974;17:331–40.CrossRefGoogle Scholar
  15. 15.
    Wang M, Yuan Q, Xie L. Mesenchymal stem cell-based immunomodulation: properties and clinical application. Stem Cells Int. 2018;2018:3057624.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Brittan M, Alison MR, Schier S, Wright NA. Bone marrow stem cell-mediated regeneration in IBD: where do we go from here? Gastroenterology. 2007;132:1171–3.CrossRefGoogle Scholar
  17. 17.
    Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB. Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am J Phys. 1999;277:183–201.CrossRefGoogle Scholar
  18. 18.
    Wang Y, Chen X, Cao W, Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol. 2014;15:1009–16.CrossRefGoogle Scholar
  19. 19.
    Keating A. Mesenchymal stromal cells. Curr Opin Hematol. 2006;13:419–25.CrossRefGoogle Scholar
  20. 20.
    Gordon JN, Pickard KM, Di Sabatino A, Prothero JD, Pender SL, Goggin PM, MacDonald TT. Matrix metalloproteinase-3 production by gut IgG plasma cells in chronic inflammatory bowel disease. Inflamm Bowel Dis. 2008;14:195–203.CrossRefGoogle Scholar
  21. 21.
    Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, Galun E, Rachmilewitz J. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood. 2005;105:2214–9.CrossRefGoogle Scholar
  22. 22.
    Gratwohl A, Passweg J, Gerber I, Tyndall A. Stem cell transplantation for autoimmune diseases. Best Pract Res Clin Haematol. 2001;14:755–76.CrossRefGoogle Scholar
  23. 23.
    Marmont AM. Stem cell transplantation for autoimmune disorders. Coincidental autoimmune disease in patients transplanted for conventional indications. Best Pract Res Clin Haematol. 2004;17:223–32.CrossRefGoogle Scholar
  24. 24.
    Kountouras J, Sakellari I, Tsarouchas G, et al. Autologous haematopoietic stem cell transplantation in a patient with refractory Crohn’s disease. J Crohns Colitis. 2011;5:275–6.CrossRefGoogle Scholar
  25. 25.
    Kriván G, Szabó D, Kállay K, et al. Successful autologous haematopoietic stem cell transplantation in severe, therapy-resistant childhood Crohn’s disease. Report on the first case in Hungary. Orv Hetil. 2014;155:789–92.CrossRefGoogle Scholar
  26. 26.
    Ruiz MA, Kaiser Junior RL, de Quadros LG, et al. Hematopoietic stem cell transplantation in a severe refractory Crohn’s disease patient with intestinal stoma: a case report. Int Med Case Rep J. 2017;10:353–9.CrossRefGoogle Scholar
  27. 27.
    Drakos PE, Nagler A, Or R. Case of Crohn’s disease in bone marrow transplantation. Am J Hematol. 1993;43:157–8.CrossRefGoogle Scholar
  28. 28.
    Gratwohl A, Passweg J, Bocelli-Tyndall C, et al. Autologous hematopoietic stem cell transplantation for autoimmune diseases. Bone Marrow Transplant. 2005;35:869–79.CrossRefGoogle Scholar
  29. 29.
    Oyama Y, Craig RM, Traynor AE, et al. Autologous hematopoietic stem cell transplantation in patients with refractory Crohn’s disease. Gastroenterology. 2005;128:552–63.CrossRefGoogle Scholar
  30. 30.
    Cassinotti A, Annaloro C, Ardizzone S, et al. Autologous haematopoietic stem cell transplantation without CD34+ cell selection in refractory Crohn’s disease. Gut. 2008;57:211–7.CrossRefGoogle Scholar
  31. 31.
    Burt RK, Craig RM, Milanetti F, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up. Blood. 2010;116:6123–32.CrossRefGoogle Scholar
  32. 32.
    Hommes DW, Duijvestein M, Zelinkova Z, et al. Long-term follow-up of autologous hematopoietic stem cell transplantation for severe refractory Crohn’s disease. J Crohns Colitis. 2011;5:543–9.CrossRefGoogle Scholar
  33. 33.
    Snowden JA, Panés J, Alexander T, European Crohn’s and Colitis Organisation (ECCO), European Society for Blood and Marrow Transplantation (EBMT), Autoimmune Diseases Working Party (ADWP), Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and EBMT (JACIE), et al. Autologous Haematopoietic Stem Cell Transplantation (AHSCT) in severe crohn’s disease: a review on behalf of ECCO and EBMT. J Crohns Colitis. 2018;12:476–88.CrossRefGoogle Scholar
  34. 34.
    López-García A, Rovira M, Jauregui-Amezaga A, et al. Autologous haematopoietic stem cell transplantation for refractory Crohn’s disease: efficacy in a single-centre cohort. J Crohns Colitis. 2017;11:1161–8.CrossRefGoogle Scholar
  35. 35.
    Hawkey CJ, Allez M, Clark MM, et al. Autologous hematopoietic stem cell transplantation for refractory Crohn disease: a randomized clinical trial. JAMA. 2015;314:2524–34.CrossRefGoogle Scholar
  36. 36.
    Burt RK, Ruiz MA, Kaiser RL Jr. Stem cell transplantation for refractory Crohn disease. JAMA. 2016;315:2620.CrossRefGoogle Scholar
  37. 37.
    Hawkey CJ, Lindsay J, Gribben J. Stem cell transplantation for refractory Crohn disease–reply. JAMA. 2016;315:2620–1.CrossRefGoogle Scholar
  38. 38.
    Lindsay JO, Allez M, Clark M, ASTIC trial group, European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party, European Crohn’s and Colitis Organisation, et al. Autologous stem-cell transplantation in treatment-refractory Crohn’s disease: an analysis of pooled data from the ASTIC trial. Lancet Gastroenterol Hepatol. 2017;2:399–406.CrossRefGoogle Scholar
  39. 39.
    Rabian F, Porcher R, Sicre de Fontbrune F, French Society of Bone Marrow Transplantation and Cell Therapy, et al. Influence of previous inflammatory bowel disease on the outcome of allogeneic hematopoietic stem cell transplantation: a matched-pair analysis. Biol Blood Marrow Transplant. 2016;22:1721–4.CrossRefGoogle Scholar
  40. 40.
    Mayne CG, Williams CB. Induced and natural regulatory T cells in the development of inflammatory bowel disease. Inflamm Bowel Dis. 2013;19:1772–88.CrossRefGoogle Scholar
  41. 41.
    Stappenbeck TS, Miyoshi H. The role of stromal stem cells in tissues regeneration and wound repair. Science. 2009;324:1666–9.CrossRefGoogle Scholar
  42. 42.
    Ditschkowski M, Einsele H, Schwerdtfeger R, et al. Improvement of inflammatory bowel disease after allogeneic stem-cell transplantation. Transplantation. 2003;75:1745–7.CrossRefGoogle Scholar
  43. 43.
    Tsuchiya A, Kojima Y, Ikarashi S, et al. Clinical trials using mesenchymal stem cells in liver diseases and inflammatory bowel diseases. Inflamm Regen. 2017;37:16.CrossRefGoogle Scholar
  44. 44.
    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;149:918–27.CrossRefGoogle Scholar
  45. 45.
    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;59:1662–9.CrossRefGoogle Scholar
  46. 46.
    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;60:788–98.CrossRefGoogle Scholar
  47. 47.
    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.CrossRefGoogle Scholar
  48. 48.
    Taupin P. OTI-010 Osiris Therapeutics/JCR pharmaceuticals. Curr Opin Investig Drugs. 2006;7:473–81.PubMedGoogle Scholar
  49. 49.
    Gazouli M, Roubelakis MG, Theodoropoulos GE. Stem cells as potential targeted therapy for inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:952–5.CrossRefGoogle Scholar
  50. 50.
    Hu J, Zhao G, Zhang L, et al. Safety and therapeutic effect of mesenchymal stem cell infusion on moderate to severe ulcerative colitis. Exp Ther Med. 2016;12:2983–9.CrossRefGoogle Scholar
  51. 51.
    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;12:73–8.CrossRefGoogle Scholar
  52. 52.
    Kim Y. Can umbilical cord mesenchymal stem cells treatment be a hope for patients with refractory Crohn’s disease? Gut Liver. 2018;12:5–6.CrossRefGoogle Scholar
  53. 53.
    Mayer L, Pandak WM, Melmed GY, et al. Safety and tolerability of human placenta-derived cells (PDA001) in treatment-resistant Crohn’s disease: a phase 1 study. Inflamm Bowel Dis. 2013;19:754–60.CrossRefGoogle Scholar
  54. 54.
    Zhang XM, Zhang YJ, Wang W, Wei YQ, Deng HX. Mesenchymal stem cells to treat Crohn’s disease with fistula. Hum Gene Ther. 2017;28:534–40.CrossRefGoogle Scholar
  55. 55.
    García-Olmo D, García-Arranz M, Herreros D, et al. A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005;48:1416–23.CrossRefGoogle Scholar
  56. 56.
    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.CrossRefGoogle Scholar
  57. 57.
    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 Color Dis. 2012;27:595–600.CrossRefGoogle Scholar
  58. 58.
    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;22:279–85.CrossRefGoogle Scholar
  59. 59.
    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;31:2575–81.CrossRefGoogle Scholar
  60. 60.
    Cho 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;4:532–7.CrossRefGoogle Scholar
  61. 61.
    Wainstein C, Quera R, Kronberg U, et al. Mesenchymal stem cells and platelet-rich plasma in the treatment of patients with perineal Crohn’s disease. Int J Color Dis. 2016;31:725–6.CrossRefGoogle Scholar
  62. 62.
    Wainstein C, Quera R, Fluxá D, et al. Stem cell therapy in refractory perineal crohn’s disease: long-term follow-up. Colorectal Dis. 2018 Jan 6. (in press).Google Scholar
  63. 63.
    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;388:1281–90.CrossRefGoogle Scholar
  64. 64.
    Press release. TiGenix and Takeda announce Alofisel® (darvadstrocel) receives approval to treat complex perianal fistulas in Crohn’s disease in Europe. 2018 Mar 23. Available at: http://tigenix.com/wp-content/uploads/2018/03/20180323-TiGenix-Takeda-EC-approval-PR-ENG-FINAL-clean.pdf.
  65. 65.
    Wei H, Liu X, Ouyang C, Zhang J, Chen S, Lu F, Chen L. Complications following stem cell therapy in inflammatory bowel disease. Curr Stem Cell Res Ther. 2017;12:471–5.CrossRefGoogle Scholar
  66. 66.
    Røsland GV, Svendsen A, Torsvik A, et al. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res. 2009;69:5331–9.CrossRefGoogle Scholar
  67. 67.
    Bernardo ME, Zaffaroni N, Novara F, et al. Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res. 2007;67:9142–9.CrossRefGoogle Scholar
  68. 68.
    Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective. Preface Bone Marrow Transpl. 2009;44:453–5.CrossRefGoogle Scholar
  69. 69.
    Jauregui-Amezaga A, Rovira M, Marín P, et al. Improving safety of autologous haematopoietic stem cell transplantation in patients with Crohn's disease. Gut. 2016;65:1456–62.CrossRefGoogle Scholar
  70. 70.
    Conklin LS, Hanley PJ, Galipeau J, Barrett J, Bollard CM. Intravenous mesenchymal stromal cell therapy for inflammatory bowel disease: lessons from the acute graft versus host disease experience. Cytotherapy. 2017;19:655–67.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Christos Zavos
    • 1
  1. 1.Aristotle University of ThessalonikiThessalonikiGreece

Personalised recommendations