Intest Res.  2019 Jul;17(3):311-316. 10.5217/ir.2019.00043.

Stem cell-based therapy for inflammatory bowel disease

Affiliations
  • 1Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
  • 2Department of Endoscopy, Tokyo Medical and Dental University, Tokyo, Japan.
  • 3Institute of Advanced Study, Tokyo Medical and Dental University, Tokyo, Japan.
  • 4Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan. rokamoto.gast@tmd.ac.jp

Abstract

Inflammatory bowel disease (IBD) is an idiopathic, multi-etiological disease characterized by inflammation and mucosal destruction of the gastrointestinal tract. Despite the remarkable advance in immunomodulating therapies, there still remains a certain population of patients who are refractory to conventional as well as biologic therapies and fail to achieve mucosal healing. To improve the prognosis of those patients, at least 2 types of stem cells have been tested for their potential therapeutic use. Transplantation of hematopoietic stem cells or mesenchymal stem cells have been tested in several clinical studies, but their beneficial effect still remains controversial. In this review, we would like to overview the recent clinical challenges of stem cell-based therapies in IBD and also introduce our new therapeutic plan of intestinal stem cell transplantation for IBD, based on our ex vivo intestinal organoid culture technique.

Keyword

Mucosal healing; Hematopoietic stem cell; Mesenchymal stem cell; Intestinal stem cell; Organoids

MeSH Terms

Biological Therapy
Culture Techniques
Gastrointestinal Tract
Hematopoietic Stem Cells
Humans
Inflammation
Inflammatory Bowel Diseases*
Mesenchymal Stromal Cells
Organoids
Prognosis
Stem Cell Transplantation
Stem Cells

Figure

  • Fig. 1. Intestinal epithelial cells (IECs) are the first barrier against outer environment. The gastrointestinal tract, formed of an IEC monolayer, interacts with the commensal microbiome and protects the organism from pathogenic microbes by secreting antimicrobial peptides and mucins. Further, IECs coordinate with stromal cells, including immune cells and mesenchymal cells, via antigen presentation and cytokine-mediated signaling, to maintain gastrointestinal homeostasis.

  • Fig. 2. Autologous intestinal stem cell (ISC) transplantation on IBD patients. Organoids are generated from biopsy samples taken through colonoscopy of an IBD patient, and further cultured and expanded for transplantation on the wound bed of the same patient. Transplantation is planned to be through colonoscopy.


Reference

1. Frøslie KF, Jahnsen J, Moum BA, Vatn MH; IBSEN Group. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology. 2007; 133:412–422.
Article
2. Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology. 2011; 141:1194–1201.
Article
3. Rutter M, Saunders B, Wilkinson K, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology. 2004; 126:451–459.
Article
4. Sato T, van Es JH, Snippert HJ, et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature. 2011; 469:415–418.
Article
5. Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med. 2011; 364:656–665.
Article
6. Román J, Planell N, Lozano JJ, et al. Evaluation of responsive gene expression as a sensitive and specific biomarker in patients with ulcerative colitis. Inflamm Bowel Dis. 2013; 19:221–229.
Article
7. Okamoto R, Watanabe M. Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease. J Gastroenterol. 2016; 51:11–21.
Article
8. Mashimo H, Wu DC, Podolsky DK, Fishman MC. Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science. 1996; 274:262–265.
Article
9. Manieri NA, Mack MR, Himmelrich MD, et al. Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis. J Clin Invest. 2015; 125:3606–3618.
Article
10. Yui S, Azzolin L, Maimets M, et al. YAP/TAZ-dependent reprogramming of colonic epithelium links ECM remodeling to tissue regeneration. Cell Stem Cell. 2018; 22:35–49.
Article
11. Sato T, Vries RG, Snippert HJ, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009; 459:262–265.
Article
12. Ishibashi F, Shimizu H, Nakata T, et al. Contribution of ATOH1(+) cells to the homeostasis, repair, and tumorigenesis of the colonic epithelium. Stem Cell Reports. 2018; 10:27–42.
Article
13. Suzuki K, Murano T, Shimizu H, et al. Single cell analysis of Crohn’s disease patient-derived small intestinal organoids reveals disease activity-dependent modification of stem cell properties. J Gastroenterol. 2018; 53:1035–1047.
Article
14. Oyama Y, Craig RM, Traynor AE, et al. Autologous hematopoietic stem cell transplantation in patients with refractory Crohn’s disease. Gastroenterology. 2005; 128:552–563.
Article
15. 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; 11:1161–1168.
Article
16. 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; 65:1456–1462.
Article
17. Hawkey CJ, Allez M, Clark MM, et al. Autologous hematopoetic stem cell transplantation for refractory Crohn disease: a randomized clinical trial. JAMA. 2015; 314:2524–2534.
Article
18. Ren G, Zhang L, Zhao X, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008; 2:141–150.
Article
19. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005; 105:1815–1822.
Article
20. Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006; 107:367–372.
Article
21. 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.
Article
22. 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; 388:1281–1290.
Article
23. Panés J, García-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; 154:1334–1342.
24. Yui S, Nakamura T, Sato T, et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat Med. 2012; 18:618–623.
Article
Full Text Links
  • IR
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr