The Role of Stem Cells in the Treatment of Anal Fistulas

  • George E. Theodoropoulos
  • Efterpi Mihailidou
  • Georgios N. Kolovos
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


The (peri)anal fistula or fistula-in-ano is defined as an abnormal channel between the anal canal and the surrounding structures, usually the perianal skin. In many occasions anal fistula treatment may become challenging. Available surgical methods are still plagued by recurrences and may be related to varying degrees of fecal incontinence. Except for the complex cases of idiopathic anal fistulas, the results provided by current medical and surgical approaches for the difficult to treat Crohn’s disease-related fistulas remain rather disappointing. In addition to their several applications, mesenchymal stromal cells (MSCs) injection in the fistula tract has arisen as a novel method with potential to manage this difficult entity. Their anti-inflammatory and immune-regulatory properties play major role at their use as a proposed treatment modality for anal fistulas. This chapter focuses on the methods of isolation and application of both autologous and allogeneic MSCs, described by the groups experienced in their use at anal fistulas, as well as on the analysis of published series, with emphasis on MSC efficacy and likely side effects. Existing studies suggest that both adipose tissue and bone marrow have been used as sources for MSCs in clinical trials for treatment of anal fistulas. Except for two phase III clinical trials, all the rest in this field were conducted as phase I and II, aiming at safety and efficacy of MSCs. MSCs have been proven safe for clinical practice, and they can be currently used alone or as an adjunct to conventional surgical treatments for complex anal fistulas.


Anal fistula Fistula-in-ano Mesenchymal stem cells Autologous stem cells Allogeneic stem cells Crohn’s disease Adipose-derived stem cells 


  1. 1.
    Han KS, Cho HM, Kim DH, Kim JG. Retrospective analysis of a fistula-in-ano: focus on an anal sphincter-preserving procedure. J Kor Soc Coloproctol. 2007;23:403–9.CrossRefGoogle Scholar
  2. 2.
    Whiteford MH, Kilkenny J, Hyman N, et al. Practice parameters for the treatment of perianal abscess and fistula-in-ano (revised). Dis Colon Rectum. 2005;48:1337–42.CrossRefGoogle Scholar
  3. 3.
    Sangwan YP, Schoetz DJ Jr, Murray JJ, Roberts PL, Coller JA. Perianal Crohn’s disease: results of local surgical treatment. Dis Colon Rectum. 1996;39:529–35.CrossRefGoogle Scholar
  4. 4.
    Zanotti C, Martinez-Puente C, Pascual I, Pascual M, Herreros D, García-Olmo D. An assessment of the incidence of fistula-in-ano in four countries of the European Union. Int J Color Dis. 2007;22:1459–62.CrossRefGoogle Scholar
  5. 5.
    Sainio P. Fistula-in-ano in a defined population. Incidence and epidemiological aspects. Ann Chir Gynaecol. 1984;73:219–24.PubMedGoogle Scholar
  6. 6.
    Scoglio D, Walker AS, Fichera A. Biomaterials in the treatment of anal fistula: hope or hype? Clin Colon Rectal Surg. 2014;27:172–81.CrossRefGoogle Scholar
  7. 7.
    Pommaret E, Benfredj P, Soudan D, de Parades V. Sphincter-sparing techniques for fistulas-in-ano. J Visc Surg. 2015;152:S31–6.CrossRefGoogle Scholar
  8. 8.
    Hwang SH, Bang MJ. Surgery for a complex anal fistula. J Kor Soc Coloproctol. 2008;24:77–82.CrossRefGoogle Scholar
  9. 9.
    Sandborn WJ, Fazio VW, Feagan BG, Hanauer SB. AGA technical review on perianal Crohn’s disease. Gastroenterology. 2003;125:1508–30.CrossRefGoogle Scholar
  10. 10.
    Parks AG, Gordon PH, Hardcastle JD. A classification of fistula-in- ano. Br J Surg. 1976;63:1–12.CrossRefGoogle Scholar
  11. 11.
    Sheedy SP, Bruining DH, Dozois EJ, Faubion WA, Fletcher JG. MR imaging of perianal Crohn disease. Radiology. 2017;282:628–45.CrossRefGoogle Scholar
  12. 12.
    Horsthuis K, Ziech ML, Bipat S, Spijkerboer AM, de Bruine-Dobben AC, Hommes DW, Stoker J. Evaluation of an MRI-based score of disease activity in perianal fistulizing Crohn’s disease. Clin Imaging. 2011;35:360–5.CrossRefGoogle Scholar
  13. 13.
    Panes J, Bouhnik Y, Reinisch W, Stoker J, et al. Imaging techniques for assessment of inflammatory bowel disease: joint ECCO and ESGAR evidence based consensus guidelines. J Crohns Colitis. 2013;7:556–85.CrossRefGoogle Scholar
  14. 14.
    Zawadzki A, Starck M, Bohe M, Thorlacius H. A unique 3D endoanal ultrasound feature of perianal Crohn’s fistula: the ‘Crohn ultrasound fistula sign. Color Dis. 2012;14:608–11.CrossRefGoogle Scholar
  15. 15.
    Schwartz DA, Ghazi LJ, Regueiro M, Fichera A, et al. Guidelines for the multidisciplinary management of Crohn’s perianal fistulas: summary statement. Inflamm Bowel Dis. 2015;21:723–30.CrossRefGoogle Scholar
  16. 16.
    Irvine EJ. Usual therapy improves perianal Crohn’s disease as measured by a new disease activity index. McMaster IBD Stud Group J Clin Gastroenterol. 1995;20:27–32.Google Scholar
  17. 17.
    Allan A, Linares L, Spooner HA, Alexander-Williams J. Clinical index to quantitate symptoms of perianal Crohn’s disease. Dis Colon Rectum. 1992;35:656–61.CrossRefGoogle Scholar
  18. 18.
    Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med. 1999;340:1398–405.CrossRefGoogle Scholar
  19. 19.
    Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350:876–85.CrossRefGoogle Scholar
  20. 20.
    Gionchetti P, Dignass A, Danese S, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: part 2: surgical management and special situations. J Crohns Colitis. 2017;11:135–49.CrossRefGoogle Scholar
  21. 21.
    Thia KT, Mahadevan U, Feagan BG, et al. Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn’s disease: a randomized, double-blind, placebo- controlled pilot study. Inflamm Bowel Dis. 2009;15:17–24.CrossRefGoogle Scholar
  22. 22.
    Westerterp M, Volkers NA, Poolman RW, van Tets WF. Anal fistulotomy between Skylla and Charybdis. Color Dis. 2003;5:549–51.CrossRefGoogle Scholar
  23. 23.
    van der Hagen SJ, Baeten CG, Soeters PB, van Gemert WG. Long-term outcome following mucosal advancement flap for high perianal fistulas and fistulotomy for low perianal fistulas: recurrent perianal fistulas: failure of treatment or recurrent patient disease? Int J Color Dis. 2006;21:784–90.CrossRefGoogle Scholar
  24. 24.
    Faucheron JL, Saint-Marc O, Guibert L, Parc R. Long- term seton drainage for high anal fistulas in Crohn’s disease—a sphincter-saving operation? Dis Colon Rectum. 1996;39:208–11.CrossRefGoogle Scholar
  25. 25.
    Thornton M, Solomon MJ. Long-term indwelling seton for complex anal fistulas in Crohn’s disease. Dis Colon Rectum. 2005;48:459–63.CrossRefGoogle Scholar
  26. 26.
    Rojanasakul A, Pattanaarun J, Sahakitrungruang C, Tantiphlachiva K. Total anal sphincter saving technique for fistula-in-ano; the ligation of intersphincteric fistula tract. J Med Assoc Thail. 2007;90:581–6.Google Scholar
  27. 27.
    Hong KD, Kang S, Kalaskar S, Wexner SD. Ligation of intersphincteric fistula tract (LIFT) to treat anal fistula: systematic review and meta-analysis. Tech Coloproctol. 2014;18:685–91.CrossRefGoogle Scholar
  28. 28.
    Shawki S, Wexner SD. Idiopathic fistula-in-ano. World J Gastroenterol. 2011;17:3277–85.CrossRefGoogle Scholar
  29. 29.
    Trebol Lopez J, Georgiev Hristov T, Garcia-Arranz M, Garcia-Olmo D. Stem cell therapy for digestive tract dis- eases: current state and future perspectives. Stem Cells Dev. 2011;20:1113–29.CrossRefGoogle Scholar
  30. 30.
    Hawkey CJ. Stem cell transplantation for Crohn’s disease. Best Pract Res Clin Haematol. 2004;17:317–25.CrossRefGoogle Scholar
  31. 31.
    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. 2017;14:153–65.CrossRefGoogle Scholar
  32. 32.
    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
  33. 33.
    Stenderup K, Justesen J, Clausen C, Kassem M. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone. 2003;33:919–26.CrossRefGoogle Scholar
  34. 34.
    Valencia J, Blanco B, Yáñez R, Vázquez M, et al. Comparative analysis of the immunomodulatory capacities of human bone marrow- and adipose tissue- derived mesenchymal stromal cells from the same donor. Cytotherapy. 2016;18:1297–311.CrossRefGoogle Scholar
  35. 35.
    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.CrossRefGoogle Scholar
  36. 36.
    Păunescu V, Deak E, Herman D, et al. In vitro differentiation of human mesenchymal stem cells to epithelial lineage. J Cell Mol Med. 2007;11:502–8.CrossRefGoogle Scholar
  37. 37.
    Hocking AM, Gibran NS. Mesenchymal stem cells: paracrine signaling and differentiation during cutaneous wound repair. Exp Cell Res. 2010;15:2213–9.CrossRefGoogle Scholar
  38. 38.
    Liang L, Dong C, Chen X, et al. Human umbilical cord mesenchymal stem cells ameliorate mice trinitrobenzene sulfonic acid [TNBS]-induced colitis. Cell Transplant. 2011;20:1395–408.CrossRefGoogle Scholar
  39. 39.
    Tao H, Han Z, Chao Han ZC, Li Z. Proangiogenic features of mesenchymal stem cells and their therapeutic applications. Stem Cells Int. 2016;2016:1314709.CrossRefGoogle Scholar
  40. 40.
    Oswald J, Boxberger S, Jørgensen B, Feldmann S, Ehninger G, Bornhäuser M, Werner C. Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells. 2004;22:377–84.CrossRefGoogle Scholar
  41. 41.
    Janeczek Portalska K, Leferink A, Groen N, Fernandes H, Moroni L, Blitterswijk v, Jan de Boer C. Endothelial differentiation of mesenchymal stromal cells. PLoS One. 2012;7:e46842.CrossRefGoogle Scholar
  42. 42.
    Voswinkel J, Francois S, Simon JM, et al. Use of mesenchymal stem cells (MSC) in chronic inflammatory fistulizing and fibrotic diseases: a comprehensive review. Clinic Rev Allerg Immunol. 2013;45:180–92.CrossRefGoogle Scholar
  43. 43.
    Nasef A, Zhang YZ, Mazurier C, et al. Selected Stro-1- enriched bone marrow stromal cells display a major suppressive effect on lymphocyte proliferation. Int J Lab Hematol. 2009;31:9–19.CrossRefGoogle Scholar
  44. 44.
    Nasef A, Mathieu N, Chapel A, et al. Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation. 2007;84:231–7.CrossRefGoogle Scholar
  45. 45.
    Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigenpresenting cell maturation and induce T-cell unresponsiveness. Blood. 2005;105:2214–9.CrossRefGoogle Scholar
  46. 46.
    Kong QF, Sun B, Bai SS, et al. Administration of bone marrow stromal cells ameliorates experimental autoimmune myasthenia gravis by altering the balance of Th1/Th2/Th17/Treg cell subsets through the secretion of TGF-beta. J Neuroimmunol. 2009;207:83–91.CrossRefGoogle Scholar
  47. 47.
    Milosavljevic N, Gazdic M, Simovic Markovic B, Arsenijevic A, Nurkovic J, Dolicanin Z, Jovicic N, Jeftic I, Djonov V, Arsenijevic N, Lukic ML, Volarevic V. Mesenchymal stem cells attenuate liver fibrosis by suppressing Th17 cells. Transpl Int. 2017;31:102–15.CrossRefGoogle Scholar
  48. 48.
    Garcia-Olmo D, Garcia-Arranz M, Herreros D. Expanded adipose-derived stem cells for the treatment of complex perianal fistula including Crohn’s disease. Expert Opin Biol Ther. 2008;8:1417–23.CrossRefGoogle Scholar
  49. 49.
    Vasandan AB, Jahnavi S, Shashank C, Prasad P, Kumar A, Prasanna SJ. Human mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE2-dependent mechanism. Sci Rep. 2016;6:38308.CrossRefGoogle Scholar
  50. 50.
    Borowski D, Gill T, Agarwal A, Bhaskar P. Autologous adipose-tissue derived regenerative cells for the treatment of complex cryptoglandular fistula-in-ano: a report of three cases. BMJ Case Rep. 2012;9:2012.Google Scholar
  51. 51.
    Borowski DW, Gill TS, Agarwal AK, Tabaqchali MA, Garg DK, Bhaskar P. Adipose tissue–derived regenerative cell–enhanced lipofilling for treatment of cryptoglandular fistulae-in-ano: the ALFA technique. Surg Innov. 2015;22:593–600.CrossRefGoogle Scholar
  52. 52.
    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
  53. 53.
    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
  54. 54.
    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
  55. 55.
    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 Color Dis. 2013;28:313–23.CrossRefGoogle Scholar
  56. 56.
    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
  57. 57.
    Molendijk I, Bonsing BA, Roelofs H, et al. Allogeneic bone marrow L derived mesenchymal stromal cells, promote healing of refractory perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2015;149:918–27.CrossRefGoogle Scholar
  58. 58.
    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;21:345–53.CrossRefGoogle Scholar
  59. 59.
    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. Color Dis. 2015;18:468–76.CrossRefGoogle Scholar
  60. 60.
    Piejko M, Romaniszyn M, Borowczyk-Michałowska J, Drukała J, Wałęga P. Cell therapy in surgical treatment of fistulas. Pol Przegl Chir. 2017;89:48–51.CrossRefGoogle Scholar
  61. 61.
    Guadalajara H, García-Arranz M, Georgiev-Hristov T, Cortés D, García-Olmo D. Prospect of cell therapy for treating perianal fistula, including Crohn’s disease. Int J Stem Cell Res Ther. 2016;3:028.Google Scholar
  62. 62.
    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.CrossRefGoogle Scholar
  63. 63.
    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.CrossRefGoogle Scholar
  64. 64.
    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
  65. 65.
    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;55:762–77.CrossRefGoogle Scholar
  66. 66.
    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;21:3330–6.CrossRefGoogle Scholar
  67. 67.
    Panés J, García-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
  68. 68.
    Dietz AB, Dozois EJ, Fletcher JG, et al. Autologous mesenchymal stem cells, applied in a bioabsorbable matrix, for treatment of perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2017;153:59–62.CrossRefGoogle Scholar
  69. 69.
    Qiu Υ, Li Μ, Feng Τ, Feng R, Mao R, Chen B, He Y, Zeng Z, Zhang S, Chen M. Systematic review with meta-analysis: the efficacy and safety of stem cell therapy for Crohn’s disease. Stem Cell Res Ther. 2017;8:136.CrossRefGoogle Scholar
  70. 70.
    Lightner AL, Wang Z, Zubair AC, Dozois EJ. 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;61:629–40.CrossRefGoogle Scholar
  71. 71.
    Garcia-Olmo D, Garcia-Arranz M, Garcia LG, Cuellar ES, Blanco IF, Prianes LA, 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 Color Dis. 2003;18:451–4.CrossRefGoogle Scholar
  72. 72.
    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;5:1441–6.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • George E. Theodoropoulos
    • 1
  • Efterpi Mihailidou
    • 1
  • Georgios N. Kolovos
    • 1
    • 2
  1. 1.Medical School, National and Kapodistrian University of AthensAthensGreece
  2. 2.Colorectal Unit, First Department of Propaedeutic Surgery, Medical SchoolNational and Kapodistrian University of AthensAthensGreece

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