Can a Conversation Between Mesenchymal Stromal Cells and Macrophages Solve the Crisis in the Inflamed Intestine?

Abstract

Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions of the gastrointestinal tract characterized by an exacerbated mucosal immune response. Macrophages play pivotal roles in the maintenance of gut homeostasis but they are also implicated in the pathogenesis of IBD. They are highly plastic cells and their activation state depends on the local environment. In the healthy intestine, resident macrophages display an M2 phenotype characterized by inflammatory energy, while inflammatory M1 macrophages dominate in the inflamed intestinal mucosa. In this regard, modifying the balance of macrophage populations into an M2 phenotype has emerged as a new therapeutic approach in IBD. Multipotent mesenchymal stromal cells (MSCs) have been proposed as a promising cell-therapy for the treatment of IBD, considering their immunomodulatory and tissue regenerative potential. Numerous preclinical studies have shown that MSCs can induce immunomodulatory macrophages and have demonstrated that their therapeutic efficacy in experimental colitis is mediated by macrophages with an M2-like phenotype. However, some issues have not been clarified yet, including the importance of MSC homing to the inflamed colon and/or lymphoid organs, their optimal route of administration or whether they are effective as living or dead cells. In contrast, the mechanisms behind the effect of MSCs in human IBD are not known and more data are needed regarding the effect of MSCs on macrophage polarization that would support the observation reported in the experimental models. Nevertheless, MSCs have emerged as a novel method to treat IBD that has already been proven safe and with clinical benefits that could be administered in combination with the currently used pharmacological treatments.

Cell Therapy With Mesenchymal Stem Cells Induces an Innate Immune Memory Response That Attenuates Experimental Colitis in the Long Term

“…In this sense, these studies have demonstrated that non-classical CX3CR1 + monocytes, CCR2 + monocytes, or bone marrow monocyte precursors were the progenitors of regulatory macrophages that were responsible for wound healing after intestinal injury. 33 , 34 , 44 Additionally, Quinn et al described that the inflammation induces monocyte migration and accumulation of AAMs in the peritoneal cavity which then migrate and differentiate into tissue macrophages, inducing tolerance in the long term. 45 They also suggested an immunological memory induced by the innate immune system.…”

Roles of Macrophages in the Development and Treatment of Gut Inflammation

“…These cytokines directly or indirectly affect the intestinal epithelial cells, leading to the injury or necrosis of these cells, which promotes the occurrence and development of IBD ( Figure 1 ). An over-secretion of cytokines and chronic inflammation are the typical features of IBD, with clinical symptoms of diarrhea, abdominal pain, fever, intestinal obstruction, and disability symptoms of blood or mucus or both ( Baumgart and Carding, 2007 ; Geremia et al, 2014 ; Geremia and Arancibia-Cárcamo, 2017 ; Hidalgo-Garcia et al, 2018 ; Ding et al, 2019b ). IBD occurs exclusively in the colon in ulcerative colitis and almost anywhere along the gastrointestinal tract in chronic diarrhea ( Jones et al, 2018 ).…”

IGF-1C hydrogel improves the therapeutic effects of MSCs on colitis in mice through PGE2-mediated M2 macrophage polarization

“…The largest population of macrophages in the body resides in the gastrointestinal tract, which plays pivotal roles in the maintenance of mucosal homeostasis and is also an important component of protective immunity 2 . M1 macrophages can release inflammatory cytokines to induce an inflammatory response.…”