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Mesenchymal stromal cells in inflammatory bowel disease: conspirators within the ‘colitogenic niche’?
  1. Silvio Danese1,
  2. Sergio Rutella2,
  3. Stefania Vetrano1
  1. 1IBD Centre, Gastroenterology, Humanitas Clinical and Research Centre, Milan, Italy
  2. 2Department of Pediatric Haematology/Oncology and Transfusion Medicine, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
  1. Correspondence to Dr Silvio Danese, IBD Centre, Gastroenterology, Humanitas Clinical and Research Centre, Milan 20089, Italy; sdanese{at}hotmail.com

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The term ‘stem cell niche’ refers to a spatial and temporal structure harbouring haematopoietic stem cells in close contact with accessory cell types, such as mesenchymal stromal cells (MSC). MSC were initially isolated from the bone marrow (BM) and subsequently from other sources, including adipose tissue and umbilical cord blood. MSC can be defined by phenotypic and functional criteria, and possess immunomodulating and regenerative properties that render them attractive candidates for cell therapy approaches in autoimmune and inflammatory disorders.1 ,2 MSC play a vital role in regulating haematopoiesis and give origin to crucial niche elements, such as osteoblasts, adipocytes and reticular fibroblasts.3 Intriguingly, MSC can home in to tissues in need of structural repair, where they release paracrine factors and recruit additional cell types, such as endothelial cells and macrophages.

BMMSC also regulate both innate and adaptive immune responses, leading to inhibited generation of T helper 17 (Th17) cells and promoting the reprogramming of Th17 cells into suppressive FoxP3-expressing regulatory T cells (Treg).4 Clinical trials with both locally delivered and systemic autologous BMMSC have shown promising results in terms of safety and therapeutic efficacy for patients with fistulising and luminal Crohn's disease (CD).5 ,6 Mechanistically, increased numbers of circulating and colonic Treg cells were measured in CD patients treated with locally injected BMMSC.5

Nemoto et al now establish a novel paradigm whereby murine BMMSC may nurture and retain colitogenic CD4 T cells within the BM niche through the production of interleukin 7 (IL-7).1 Previously, they had shown that colitogenic central memory CD4 T cells reside within the BM niche, in close association with IL-7-producing, BM-resident MSC.7 Also, they demonstrated that colitogenic CD4 T cells recirculate from the intestinal lamina propria to the BM.8 In this issue of Gut, BMMSC from both IL-7-sufficient and IL-7-deficient mice were shown to inhibit the in vitro proliferation of CD4CD25 T cells in response to stimulation with anti-CD3 antibodies and antigen-presenting cells. Conversely, IL-7+/+ but not IL-7−/− BMMSC promoted the survival and expansion of colitogenic CD4 T cells, an effect that was abrogated by anti-IL-7 antibodies. Importantly, IL-7−/−×recombination activating gene (RAG)-1−/− mice pretransplanted with IL-7-sufficient BMMSC developed colitis after adoptive transfer of CD4CD45RBhi T cells. T cells isolated from colitic mice displayed a CD44CD62LCD69IL-7Rαhi effector memory phenotype and released high amounts of proinflammatory interferon-γ, tumor necorsis factor-α and IL-17. Of relevance, IL-7 mRNA and protein were exclusively detected within the BM. The pathogenetic role of BMMSC was further corroborated by experiments where BMMSC were cotransplanted with colitogenic CD4 T cells to RAG-2−/− mice. In this setting, BMMSC failed to suppress colitis as measured through histological and clinical scores.

This scenario prompts a rethinking of inflammatory bowel disease as a systemic disease, and suggests that the role of BMMSC in the regulation of inflammation may be more complex and multifaceted than traditionally appreciated (figure 1). The Janus face of BMMSC is exemplified by the observation that they may serve either an anti-inflammatory or a proinflammatory role, depending on their interaction with other cell types and/or soluble factors within the BM niche. It is tempting to speculate that the route of MSC delivery, that is, intrarectal versus systemic, may affect their functional state and in vivo efficacy. Future clinical trials with MSC in CD patients will hopefully provide an answer to this question by measuring IL-7 levels before and after MSC infusion.

Figure 1

Dual roles for bone marrow mesenchymal stromal cells (BMMSC) in inflammation and autoimmunity. BMMSC may play a divergent role within the BM niche. Conventionally, BMMSC have been viewed as general suppressors of both innate and adaptive immune responses. A constellation of mechanisms underpin the anti-inflammatory and immunomodulating effects of BMMSC, including the activation of tryptophan catabolism by indoleamine 2,3-dioxygenase, the release of immunosuppressive cytokines, including transforming growth factor-β, hepatocyte growth factor and prostaglandin E2 production by cyclooxygenase, all of which lead to Treg expansion/differentiation. Intriguingly, as yet unknown inflammatory stimuli might incite IL-7 production by BMMSC, resulting in expansion and enhanced survival of colitogenic central memory T cells and leading to inflammatory bowel disease. Effector memory T cells may also reside within the BM niche.

The study by Nemoto et al points to IL-7 as a molecular determinant of pathogenic T cell persistence, as it shows that, at least in a T cell transfer model of colitis, BMMSC-derived IL-7 fosters T cell homeostatic expansion and survival.1 However, IL-7 may be necessary for Treg homeostasis also. It is presently unknown whether IL-7 blockade can be safely developed in the clinic with the aim of shrinking the reservoir of BM-resident colitogenic CD4 T cells without ‘suppressing the suppressors’ and allowing the expansion of autoreactive and/or alloreactive T cells.9 In this respect, blocking IL-7 receptor α (IL-7Rα) with monoclonal antibodies has been shown to prevent autoimmune diabetes in nonobese diabetic/severe combined immune deficient mice, tipping the balance between pathogenic effector memory T cells and Treg cells in favour of the latter cell type.10 It remains to be determined whether human BMMSC are endowed with the ability to support the homeostatic proliferation of pathogenic T cells through the production of IL-7 or other microenvironmental T cell-targeting growth factors. In conclusion, the study published by Nemoto et al raises exciting implications for the treatment of human inflammatory bowel disease, and possibly other T cell-mediated disorders, with IL-7 blockade. It is imperative that the role of MSC-derived IL-7 in the maintenance of pathogenic T cells within the BM niche be confirmed soon in humans.

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Footnotes

  • Contributors All the authors wrote and edited the commentary.

  • Funding None.

  • Competing interests None.

  • Provenance and peer review Commissioned; internally peer reviewed.

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