Intestinal mesenchymal cells regulate immune responses and promote epithelial regeneration in vitro and in dextran sulfate sodium‐induced experimental colitis in mice

Abstract

Aim Disruption of the intestinal mucosal tolerance, that is, the immunological unresponsiveness to innocuous food antigens and the commensal microbiota, in the colon is associated with several chronic diseases including inflammatory bowel disease (IBD). Understanding the mechanisms responsible for intestinal mucosal tolerance has potential translational value for its therapy and management. Human intestinal mesenchymal cells (iMCs) play important roles in colonic mucosal tolerance, but further studies on their tissue regenerative and immunomodulatory capacities are necessary in order to fully understand their function in health and disease. Methods In this study, we have isolated and analysed the capacity of human iMCs to promote wound healing and modulate immune responses in vitro and in vivo, using the dextran sulfate sodium (DSS)‐induced colitis model. Results Cultured iMCs were CD45−CD73+CD90+CD105+ and accelerated the wound closure in a normal colon mucosa (NCM) 356 human epithelial cell wound healing assay. Furthermore, iMCs blocked the LPS‐mediated induction of TNF‐α in THP‐1 macrophages and inhibited the proliferation of peripheral blood mononuclear cells, partly through the induction of indoleamine‐2,3‐dioxygenase. In DSS colitic mice, iMCs administration reduced the disease activity index and ameliorated intestinal tissue damage and permeability. Furthermore, iMCs reduced intestinal inflammation, evidenced by a decreased mRNA expression of pro‐inflammatory cytokines, reduced IL‐1β secretion by intestinal explants and inhibited colonic iNOS protein expression. Conclusions Our data show that human iMCs isolated from the noninflamed intestine possess tissue‐regenerative and immunomodulatory capacities that could potentially be harnessed/restored in order to reduce IBD severity.

Immunomodulatory effects of intestinal mesenchymal cells in the context of inflammatory bowel disease

“…Overall, this published study 1 has demonstrated significant potential for iMCs to preserve epithelial integrity and dampen an inflammatory response in an animal model of severe colitis. This protective action involves down-regulating inflammation via suppressing the action of IL-1β linked to IDO-1 (although the precise mechanism of action for the latter haem protein is yet to be established as it was unclear whether protein-protein interactions or the products of IDO-1 enzymic activity were involved).…”

“…In this highlighted study, 1 intestinal mesenchymal cells were sourced from human resected intestine and following enzymatic digestion isolated human cells were sub‐cultured further. Completely consistent with the study design these cultured cells exhibited a fibroblast‐like morphology while lacking haemopoietic, epithelial and endothelial markers (including CD45, CD31, EpCAM and CD 34 respectively).…”

“…Herein, we report on a recent innovative study by Hidalgo‐Garcia and colleagues published in this issue 1 . This study describes an investigation on the immunomodulatory effects of intestinal mesenchymal cells and their role in maintaining epithelial integrity in vitro and mitigating the course of dextran sodium sulphate (DSS)–mediated colitis in vivo.…”

Macrophage orchestration of epithelial and stromal cell homeostasis in the intestine

“…Therapeutic interventions via mesenchymal cell‐macrophage crosstalk disruption have also been reported. CD45 − CD73 + CD90 + CD105 + intestinal mesenchymal cells blunted macrophage production of inflammatory cytokines in colitis 259 . Furthermore, bone marrow mesenchymal stem cells (MSC) reduced severity of colitis through secretion of TSG6, facilitating the accumulation of IL‐10‐producing macrophages 260 .…”

“…CD45 − CD73 + CD90 + CD105 + intestinal mesenchymal cells blunted macrophage production of inflammatory cytokines in colitis. 259 Furthermore, bone marrow mesenchymal stem cells (MSC) reduced severity of colitis through secretion of TSG6, facilitating the accumulation of IL-10-producing macrophages. 260 In another work, the anticolitic role of MSCs was attributed to extracellular vesicles.…”