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Stem Cell Transplantation for Autoimmune Diseases and Inflammation pp 125–138Cite as

Use of Mesenchymal Stem Cells in Inflammatory Bowel Disease

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Part of the book series: Stem Cells in Clinical Applications ((SCCA))

Abstract

Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the gastrointestinal tract that are characterized by phases of exacerbation and remission. Currently available therapeutics are unable to completely invert inflammation in the gastrointestinal tract of IBD patients. Accordingly, novel therapeutic approaches for the treatment of IBD are urgently needed.

Mesenchymal stem cells (MSCs) are self-renewable, multipotent cells capable to suppress immune response and to differentiate into gastrointestinal epithelial cells. MSC-mediated suppression of intestinal inflammation and, at the same time, MSC-dependent regeneration of gut epithelium were responsible for their beneficial effects in the therapy of IBD patients. As demonstrated by several already completed clinical trials, local transplantation of MSCs is safe and efficient approach for the healing of perianal fistulas while systemic administration of MSCs may result in either attenuation or aggravation of IBDs. In this chapter we emphasize current knowledge and future perspectives related to the use of MSCs in the therapy of IBDs.

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References

  1. Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003;3:521–33.

    Article  CAS  Google Scholar 

  2. Orholm M, Munkholm P, Langholz E, Nielsen OH, Sørensen TI, Binder V. Familial occurrence of inflammatory bowel disease. N Engl J Med. 1991;324:84–8.

    Article  CAS  Google Scholar 

  3. Monsén U, Broström O, Nordenvall B, Sörstad J, Hellers G. Prevalence of inflammatory bowel disease among relatives of patients with ulcerative colitis. Scand J Gastroenterol. 1987;22:214–8.

    Article  Google Scholar 

  4. Farmer RG, Michener WM, Mortimer EA. Studies of family history among patients with inflammatory bowel disease. Clin Gastroenterol. 1980;9:271–7.

    CAS  PubMed  Google Scholar 

  5. Tysk C, Lindberg E, Järnerot G, Flodérus-Myrhed B. Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the infl uence of smoking. Gut. 1988;29:990–6.

    Article  CAS  Google Scholar 

  6. Orholm M, Binder V, Sørensen TI, Rasmussen LP, Kyvik KO. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol. 2000;35:1075–81.

    Article  CAS  Google Scholar 

  7. Beaugerie L, Massot N, Carbonnel F, Cattan S, Gendre JP, Cosnes J. Impact of cessation of smoking on the course of ulcerative colitis. Am J Gastroenterol. 2001;96:2113–6.

    Article  CAS  Google Scholar 

  8. García Rodríguez LA, Ruigómez A, Panés J. Acute gastroenteritis is followed by an increased risk of inflammatory bowel disease. Gastroenterology. 2006;130:1588–94.

    Article  Google Scholar 

  9. Porter CK, Tribble DR, Aliaga PA, Halvorson HA, Riddle MS. Infectious gastroenteritis and risk of developing inflammatory bowel disease. Gastroenterology. 2008;135:781–6.

    Article  Google Scholar 

  10. Loddo I, Romano C. Inflammatory bowel disease: genetics, epigenetics, and pathogenesis. Front Immunol. 2015;6:551.

    Article  Google Scholar 

  11. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–34.

    Article  CAS  Google Scholar 

  12. Thomas A, Lodhia N. Advanced therapy for inflammatory bowel disease: a guide for the primary care physician. J Am Board Fam Med. 2014;27:411–20.

    Article  Google Scholar 

  13. Markovic BS, Kanjevac T, Harrell CR, Gazdic M, Fellabaum C, Arsenijevic N, Volarevic V. Molecular and cellular mechanisms involved in mesenchymal stem cell-based therapy of inflammatory bowel diseases. Stem Cell Rev. 2018;14:153–65.

    Article  CAS  Google Scholar 

  14. Gazdic M, Volarevic V, Arsenijevic N, Stojkovic M. Mesenchymal stem cells: a friend or foe in immune-mediated diseases. Stem Cell Rev. 2015;11:280–7.

    Article  CAS  Google Scholar 

  15. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815–22.

    Article  CAS  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. Prockop DJ. Concise review: two negative feedback loops place mesenchymal stem/stromal cells at the center of early regulators of inflammation. Stem Cells. 2013;31:2042–6.

    Article  CAS  Google Scholar 

  18. Eggenhofer E, Hoogduijn MJ. Mesenchymal stem cell-educated macrophages. Transplant Res. 2012;1:12.

    Article  CAS  Google Scholar 

  19. Melief SM, Schrama E, Brugman MH, Tiemessen MM, Hoogduijn MJ, Fibbe WE, Roelofs H. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages. Stem Cells. 2013;31:1980–91.

    Article  CAS  Google Scholar 

  20. Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L, Borg C, Saas P, Tiberghien P, Rouas-Freiss N, Carosella ED, Deschaseaux F. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells. 2008;26:212–22.

    Article  CAS  Google Scholar 

  21. Păunescu V, Deak E, Herman D, Siska IR, Tănasie G, Bunu C, Anghel S, Tatu CA, Oprea TI, Henschler R, Rüster B, Bistrian R, Seifried E. In vitro differentiation of human mesenchymal stem cells to epithelial lineage. J Cell Mol Med. 2007;11:502–8.

    Article  Google Scholar 

  22. Ferrand J, Noël D, Lehours P, Prochazkova-Carlotti M, Chambonnier L, Ménard A, Mégraud F, Varon C. Human bone marrow-derived stem cells acquire epithelial characteristics through fusion with gastrointestinal epithelial cells. PLoS One. 2011;6:e19569.

    Article  CAS  Google Scholar 

  23. Schwartz DA, Loftus EV Jr, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of fistulizing Crohn’s disease in Olmsted County, Minnesota. Gastroenterology. 2002;122:875–80.

    Article  Google Scholar 

  24. 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;20:2022–8.

    Article  Google Scholar 

  25. Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, Minelli A, Alvisi C, Vanoli A, Calliada F, Dionigi P, Perotti C, Locatelli F, Corazza GR. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut. 2011;60:788–98.

    Article  Google Scholar 

  26. Molendijk I, Bonsing BA, Roelofs H, Peeters KC, Wasser MN, Dijkstra G, van der Woude CJ, Duijvestein M, Veenendaal RA, Zwaginga JJ, Verspaget HW, Fibbe WE, van der Meulen-de Jong AE, Hommes DW. Allogeneic bone marrow-derived mesenchymal stromal cells promote healing of refractory perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2015;149:918–27.

    Article  Google Scholar 

  27. García-Olmo D, García-Arranz M, García LG, Cuellar ES, Blanco IF, Prianes LA, Montes JA, Pinto FL, Marcos DH, García-Sancho L. Autologous stem cell transplantation for treatment of rectovaginal fistula in perianal Crohn’s disease: a new cell-based therapy. Int J Colorectal Dis. 2003;18:451–4.

    Article  Google Scholar 

  28. García-Olmo D, García-Arranz M, Herreros D, Pascual I, Peiro C, Rodríguez-Montes JA. A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005;48:1416–23.

    Article  Google Scholar 

  29. Garcia-Olmo D, Herreros D, Pascual I, Pascual JA, Del-Valle E, Zorrilla J, De-La-Quintana P, Garcia-Arranz M, Pascual M. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum. 2009;52:79–86.

    Article  Google Scholar 

  30. Herreros MD, Garcia-Arranz M, Guadalajara H, De-La-Quintana P, Garcia-Olmo D, FATT Collaborative Group. 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;55:762–72.

    Article  CAS  Google Scholar 

  31. Lee WY, Park KJ, Cho YB, Yoon SN, Song KH, Kim DS, Jung SH, Kim M, Yoo HW, Kim I, Ha H, Yu CS. Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn’s fistula. Stem Cells. 2013;31:2575–81.

    Article  CAS  Google Scholar 

  32. 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.

    Article  Google Scholar 

  33. de la Portilla F, Alba F, García-Olmo D, Herrerías JM, González 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;28:313–23.

    Article  Google Scholar 

  34. Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A, Nachury M, Ferrante M, Kazemi-Shirazi L, Grimaud JC, de la Portilla F, Goldin E, Richard MP, Leselbaum A, Danese S, ADMIRE CD Study Group Collaborators. 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.

    Article  Google Scholar 

  35. Duijvestein M, Vos AC, Roelofs H, Wildenberg ME, Wendrich BB, Verspaget HW, Kooy-Winkelaar EM, Koning F, Zwaginga JJ, Fidder HH, Verhaar AP, Fibbe WE, van den Brink GR, Hommes DW. 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.

    Article  Google Scholar 

  36. Dhere T, Copland I, Garcia M, Chiang KY, Chinnadurai R, Prasad M, Galipeau J, Kugathasan S. The safety of autologous and metabolically fit bone marrow mesenchymal stromal cells in medically refractory Crohn’s disease - a phase 1 trial with three doses. Aliment Pharmacol Ther. 2016;44:471–81.

    Article  CAS  Google Scholar 

  37. Wakitani S, Imoto K, Yamamoto T, Saito M, Murata N, Yoneda M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthr Cartil. 2002;10:199–206.

    Article  CAS  Google Scholar 

  38. Pers YM, Rackwitz L, Ferreira R, Pullig O, Delfour C, Barry F, Sensebe L, Casteilla L, Fleury S, Bourin P, Noël D, Canovas F, Cyteval C, Lisignoli G, Schrauth J, Haddad D, Domergue S, Noeth U, Jorgensen C, ADIPOA Consortium. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016;5:847–56.

    Article  Google Scholar 

  39. Koh YG, Kwon OR, Kim YS, Choi YJ, Tak DH. Adipose-derived mesenchymal stem cells with microfracture versus microfracture alone: 2-year follow-up of a prospective randomized trial. Arthroscopy. 2016;32:97–109.

    Article  Google Scholar 

  40. Kim JD, Lee GW, Jung GH, Kim CK, Kim T, Park JH, Cha SS, You YB. Clinical outcome of autologous bone marrow aspirates concentrate (BMAC) injection in degenerative arthritis of the knee. Eur J Orthop Surg Traumatol. 2014;24:1505–11.

    Article  Google Scholar 

  41. Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, Sentís J, Sánchez A, García-Sancho J. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation. 2013;95:1535–41.

    Article  CAS  Google Scholar 

  42. Davatchi F, Sadeghi Abdollahi B, Mohyeddin M, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients. Int J Rheum Dis. 2016;19:219–25.

    Article  Google Scholar 

  43. Vangsness CT Jr, Farr J 2nd, Boyd J, Dellaero DT, Mills CR, LeRoux-Williams M. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J Bone Joint Surg Am. 2014;96:90–8.

    Article  Google Scholar 

  44. von Bahr L, Batsis I, Moll G, Hägg M, Szakos A, Sundberg B, Uzunel M, Ringden O, Le Blanc K. Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells. 2012;30:1575–8.

    Article  Google Scholar 

  45. Volarevic V, Gazdic M, Simovic Markovic B, Jovicic N, Djonov V, Arsenijevic N. Mesenchymal stem cell-derived factors: immuno-modulatory effects and therapeutic potential. Biofactors. 2017;43:633–44.

    Article  CAS  Google Scholar 

  46. Im GI. Tissue engineering in osteoarthritis: current status and prospect of mesenchymal stem cell therapy. BioDrugs. 2018;32:183–92.

    Article  Google Scholar 

  47. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003;31:890–6.

    Article  Google Scholar 

  48. Zangi L, Margalit R, Reich-Zeliger S, Bachar-Lustig E, Beilhack A, Negrin R, Reisner Y. Direct imaging of immune rejection and memory induction by allogeneic mesenchymal stromal cells. Stem Cells. 2009;27:2865–74.

    Article  CAS  Google Scholar 

  49. Onken DJ, Gallup J, Hanson M, Pandak L. Custer. Successful outpatient treatment of refractory Crohn’s disease using adult mesenchymal stem cells. American College of Gastroenterology Conference Las Vegas, NV; 2006.

    Google Scholar 

  50. Forbes GM, Sturm MJ, Leong RW, Sparrow MP, Segarajasingam D, Cummins AG, Phillips M, Herrmann RP. 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.

    Article  Google Scholar 

  51. Cuerquis J, Romieu-Mourez R, François M, Routy JP, Young YK, Zhao J, Eliopoulos N. Human mesenchymal stromal cells transiently increase cytokine production by activated T cells before suppressing T-cell proliferation: effect of interferon-γ and tumor necrosis factor-α stimulation. Cytotherapy. 2014;16:191–202.

    Article  CAS  Google Scholar 

  52. Duijvestein M, Wildenberg ME, Welling MM, Hennink S, Molendijk I, van Zuylen VL, Bosse T, Vos AC, de Jonge-Muller ES, Roelofs H, van der Weerd L, Verspaget HW, Fibbe WE, te Velde AA, van den Brink GR, Hommes DW. Pretreatment with interferon-gamma enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis. Stem Cells. 2011;29:1549–58.

    Article  CAS  Google Scholar 

  53. Chen Y, Song Y, Miao H, Xu Y, Lv M, Wang T, Hou Y. Gene delivery with IFN-γ-expression plasmids enhances the therapeutic effects of MSCs on DSS-induced mouse colitis. Inflamm Res. 2015;64:671–81.

    Article  CAS  Google Scholar 

  54. Lindsay JO, Allez M, Clark M, Labopin M, Ricart E, Rogler G, Rovira M, Satsangi J, Farge D, Hawkey CJ, ASTIC trial group; European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party; European Crohn’s and Colitis Organisation. 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.

    Article  Google Scholar 

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Authors and Affiliations

  1. Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

    Vladislav Volarevic, Bojana Simovic Markovic & Nemanja Jovicic

  2. Regenerative Processing Plant-RPP, LLC, Palm Harbor, FL, USA

    C. Randall Harrell, Crissy Fellabaum & Nebojsa Arsenijevic

  3. Institute of Anatomy, University of Bern, Bern, Switzerland

    Valentin Djonov

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  1. Vladislav Volarevic
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  2. Bojana Simovic Markovic
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  3. C. Randall Harrell
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  4. Crissy Fellabaum
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  5. Nemanja Jovicic
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  6. Valentin Djonov
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  7. Nebojsa Arsenijevic
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  1. Laboratory of Stem Cell Research and Application, University of Science, VNU-HCM, Stem Cell Institute, University of Science, VNU-HCM, Ho Chi Minh City, Vietnam

    Phuc Van Pham

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Volarevic, V. et al. (2019). Use of Mesenchymal Stem Cells in Inflammatory Bowel Disease. In: Pham, P. (eds) Stem Cell Transplantation for Autoimmune Diseases and Inflammation. Stem Cells in Clinical Applications. Springer, Cham. https://doi.org/10.1007/978-3-030-23421-8_7

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