Current treatment approaches fail to address the underlying factors responsible for the pathogenesis of Crohn's disease (CD). Mesenchymal stromal cells (MSCs) are fibroblastic plastic adherent cells with specific surface markers, and may demonstrate trilineage differentiation ability. MSCs can be isolated from either the adipose tissue, bone marrow or umbilical cord. In refractory fistulizing CD, both autologous and allogeneic MSC therapy with repeated administrations is a feasible and safe therapeutic option with suggestion of efficacy, and several phase 3 trials are currently underway to determine its efficacy. In this review, we discuss the potential therapeutic role of MSC therapy for CD, which is predominantly related to its immunomodulatory role. The characteristics of MSCs derived from patients with CD and its pharmacological interaction are outlined. Preclinical studies using experimental models of colitis and clinical studies using MSCs for the treatment of fistulizing CD are highlighted. Finally, the current perspective and potential limitations of this novel therapy with recommendations for future studies are discussed.

Mowat C, Cole A, Windsor A, Ahmad T, Arnott I, Driscoll R, Mitton S, Orchard T, Rutter M, Younge L, Lees C, Ho GT, Satsangi J, Bloom S: Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571-607.
Nielsen OH, Rogler G, Hahnloser D, Thomsen OO: Diagnosis and management of fistulizing Crohn's disease. Nat Clin Pract Gastroenterol Hepatol 2009;6:92-106.
Liang L, Dong C, Chen X, Fang Z, Xu J, Liu M, Zhang X, Gu DS, Wang D, Du W, Zhu D, Han ZC: Human umbilical cord mesenchymal stem cells ameliorate mice trinitrobenzene sulfonic acid (TNBS)-induced colitis. Cell Transplant 2011;20:1395-1408.
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.
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.
Ryan JM, Barry FP, Murphy JM, Mahon BP: Mesenchymal stem cells avoid allogeneic rejection. J Inflamm (Lond) 2005;2:8.
Duffy MM, Ritter T, Ceredig R, Griffin MD: Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Ther 2011;2:34.
Gonzalez-Rey E, Anderson P, Gonzalez MA, Rico L, Buscher D, Delgado M: Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 2009;58:929-939.
Parekkadan B, Fletcher AL, Li M, Tjota MY, Bellemare-Pelletier A, Milwid JM, Lee JW, Yarmush ML, Turley SJ: Aire controls mesenchymal stem cell-mediated suppression in chronic colitis. Mol Ther 2012;20:178-186.
Parekkadan B, Upadhyay R, Dunham J, Iwamoto Y, Mizoguchi E, Mizoguchi A, Weissleder R, Yarmush ML: Bone marrow stromal cell transplants prevent experimental enterocolitis and require host CD11b+ splenocytes. Gastroenterology 2011;140:966-975.
Gonzalez MA, Gonzalez-Rey E, Rico L, Büscher D, Delgado M: Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology 2009;136:978-989.
Ko IK, Kim BG, Awadallah A, Mikulan J, Lin P, Letterio JJ, Dennis JE: Targeting improves MSC treatment of inflammatory bowel disease. Mol Ther 2010;18:1365-1372.
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.
Duijvestein M, Wildenberg ME, Welling MM, et al: Pretreatment with interferon-gamma enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis. Stem Cells 2011;29:1549-1558.
Tanaka F, Tominaga K, Ochi M, Tanigawa T, Watanabe T, Fujiwara Y, Ohta K, Oshitani N, Higuchi K, Arakawa T: Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodium-induced colitis via anti-inflammatory action in damaged tissue in rats. Life Sci 2008;83:771-779.
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.
Ando Y, Inaba M, Sakaguchi Y, Tsuda M, Quan GK, Omae M, Okazaki K, Ikehara S: Subcutaneous adipose tissue-derived stem cells facilitate colonic mucosal recovery from 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. Inflamm Bowel Dis 2008;14:826-838.
Tanaka H, Arimura Y, Yabana T, Goto A, Hosokawa M, Nagaishi K, Yamashita K, Yamamoto H, Sasaki Y, Fujimiya M, Imai K, Shinomura Y: Myogenic lineage differentiated mesenchymal stem cells enhance recovery from dextran sulfate sodium-induced colitis in the rat. J Gastroenterol 2011;46:143-152.
Hayashi Y, Tsuji S, Tsujii M, Nishida T, Ishii S, Iijima H, Nakamura T, Eguchi H, Miyoshi E, Hayashi N, Kawano S: Topical implantation of mesenchymal stem cells has beneficial effects on healing of experimental colitis in rats. J Pharmacol Exp Ther 2008;326:523-531.
Yabana T, Arimura Y, Tanaka H, Goto A, Hosokawa M, Nagaishi K, Yamashita K, Yamamoto H, Adachi Y, Sasaki Y, Isobe M, Fujimiya M, Imai K, Shinomura Y: Enhancing epithelial engraftment of rat mesenchymal stem cells restores epithelial barrier integrity. J Pathol 2009;218:350-359.
Wei Y, Nie Y, Lai J, Wan YJ, Li Y: Comparison of the population capacity of hematopoietic and mesenchymal stem cells in experimental colitis rat model. Transplantation 2009;88:42-48.
Bernardo ME, Avanzini MA, Ciccocioppo R, et al: Phenotypical/functional characterization of in vitro-expanded mesenchymal stromal cells from patients with Crohn's disease. Cytotherapy 2009;11:825-836.
Duijvestein M, Molendijk I, Roelofs H, Vos AC, Verhaar AP, Reinders ME, Fibbe WE, Verspaget HW, van den Brink GR, Wildenberg ME, Hommes DW: Mesenchymal stromal cell function is not affected by drugs used in the treatment of inflammatory bowel disease. Cytotherapy 2011;13:1066-1073.
Marlicz W, Zuba-Surma E, Kucia M, Blogowski W, Starzynska T, Ratajczak MZ: Various types of stem cells, including a population of very small embryonic-like stem cells, are mobilized into peripheral blood in patients with Crohn's disease. Inflamm Bowel Dis 2012;18:1711-1722.
Zhang Q, Shi S, Liu Y, Uyanne J, Shi Y, Le AD: Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis. J Immunol 2009;183:7787-7798.
Garcia-Olmo D, Garcia-Arranz M, Garcia LG, Cuellar ES, Blanco IF, Prianes LA, Montes JA, Pinto FL, Marcos DH, Garcia-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;18:451-454.
Garcia-Olmo D, Herreros D, De-La-Quintana P, Guadalajara H, Trebol J, Georgiev-Hristov T, Garcia-Arranz M: Adipose-derived stem cells in Crohn's rectovaginal fistula. Case Report Med 2010;2010:961758.
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.
Garcia-Olmo D, Herreros D, Pascual M, Pascual I, De-La-Quintana P, Trebol J, Garcia-Arranz M: 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.
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.
Garcia-Arranz M, Gomez-Pinedo U, Hardisson D, Herreros D, Guadalajara H, Garcia-Gomez I, Garcia-Verdugo JM, Garcia-Olmo D: Histopathological analysis of human specimens removed from the injection area of expanded adipose-derived stem cells. Histopathology 2010;56:979-982.
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.
Lee WY, Park KJ, Cho YB, Yoon SN, Song KH, Kim do S, 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;31:2575-2581.
Herreros MD, Garcia-Arranz M, Guadalajara H, De-La-Quintana P, Garcia-Olmo D, Group FC: 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;55:762-772.
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.
Liang J, Zhang H, Wang D, Feng X, Wang H, Hua B, Liu B, Sun L: Allogeneic mesenchymal stem cell transplantation in seven patients with refractory inflammatory bowel disease. Gut 2012;61:468-469.
Vicente Lopez MA, Vazquez Garcia MN, Entrena A, Olmedillas Lopez S, Garcia-Arranz M, Garcia-Olmo D, Zapata A: Low doses of bone morphogenetic protein 4 increase the survival of human adipose-derived stem cells maintaining their stemness and multipotency. Stem Cells Dev 2011;20:1011-1019.
Vilalta M, Degano IR, Bago J, Gould D, Santos M, Garcia-Arranz M, Ayats R, Fuster C, Chernajovsky Y, Garcia-Olmo D, Rubio N, Blanco J: Biodistribution, long-term survival, and safety of human adipose tissue-derived mesenchymal stem cells transplanted in nude mice by high sensitivity non-invasive bioluminescence imaging. Stem Cells Dev 2008;17:993-1003.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.