Mechanisms of the inflammatory activation of mesenchymal cells in ulcerative colitis

About This Grant

Abstract No curative therapy exists for ulcerative colitis (UC) due to a critical gap in knowledge regarding the mechanism(s) driving chronic inflammation in UC. The rationale for this proposal is built upon emerging evidence that (1) CD90+ mesenchymal cells, known as myo-/fibroblasts (MFs), are critical to the pathophysiology of UC, although this has not been studied extensively; (2) JAK/STAT signaling is among the key pathways that drive inflammation in IBD; (3) microbiota/stem cell interplay is suggested to be a potential avenue for therapeutic improvement of inflammatory diseases. An increase in pathological type 2 and 17 immune responses by CD4+T and NKT cells, together with abnormal interferon (IFN) signaling, is a hallmark of the inflammation in UC. Our published and preliminary data show that, under gut homeostasis, MFs act as major immunosuppressors of T/NKT cell responses. By contrast, an increase in the inflammatory population of MFs occurs in UC (UC-MFs), supporting pathological T/NKT responses in UC. Thus, we propose that MFs are among the key cells in the pathogenesis of UC. However, the mechanisms responsible for the generation/activation of inflammatory UC-MFs are unknown. We reported that abnormal differentiation of mesenchymal stem cells (MSCs) to MFs occurs in UC. Our preliminary data demonstrated an increase in JAK2 expression and activity in the population of inflammatory MFs in UC. Our initial data suggest that this abnormally high Jak2 activity is key to the pathological responses of UC-MFs and that upregulation of JAK2 expression in UC-MFs is likely to occur during differentiation from tissue-resident MSCs in response to the dysbiotic microbial ligands. MSC therapy has shown promise for treatment of moderate-to-severe UC, but about 50% of patients relapse within the first five years post therapy; the cause of this relapse is unknown. We found that depletion of dysbiotic microbiota prior to MSC treatment shows improved outcome in a preclinical animal model of UC. Thus, we hypothesize that overexpression of JAK2 is key to the pathological activation of UC-MFs, that MyD88-dependent activation of MF progenitors (MSCs) by dysbiotic microbial ligands is a critical event in the generation of Jak2high UC- MFs, and these processes have potential as therapeutic targets. Three specific aims are proposed: (1) Define mechanism(s) by which overexpression of JAK2 contributes to the inflammatory activation of MFs in UC.; (2) Define the role of microbial ligand-dependent MyD88 signaling in the mechanism(s) of upregulation of JAK2 expression within progenitors of MFs and the generation of Jak2high UC-MFs; (3) Evaluate how microbial dysbiosis impacts MSC therapy effectiveness and MSC-mediated replacement of Jak2high UC-MFs in preclinical animal models of UC. We expect to define the novel mechanisms contributing to the pathological activation of mesenchymal cells in UC and to provide a scientific, preclinical basis for the development of specific pathway-mediated, combined mesenchymal cell/microbiota therapeutic approaches.