Disruption of Immunoregulatory Functions of Intestinal Mesenchymal Stromal Cells and their Progenitors in Inflammatory Bowel Disease

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Crohn’s Disease (CD) and Ulcerative Colitis (UC), the two major forms of Inflammatory Bowel Disease (IBD), are multifactorial autoimmune diseases caused by an abnormal immune response to gut microbiota in genetically susceptible individuals resulting in dysregulation of type 1/2/17 immune responses. CD90+ (myo)fibroblasts (CMFs) are abundant innate immune cells in normal colonic mucosa that express Programmed Death-Ligands 1 & 2 (PD-L1/2) to promote immune tolerance. However, PD-L1 signaling is altered in IBD for as yet unknown reasons. Gremlin 1+ (Grem1) Mesenchymal Stromal progenitor Cells (MSCs) are progenitors of CMFs under homeostasis, but their fate during IBD immunopathogenesis is unknown. I hypothesize that PD-L1 expressed by CMFs is a critical driver of immune imbalance in IBD and that CMFs developed altered PD-L1 expression due to the sensitivity of their progenitor MSCs to the IBD inflammatory milieu. This dissertation utilizes various in vitro and in situ experiments to determine the role of altered PD-L1 signaling by CMFs in driving altered type 1/2/17 immune responses and investigating the role of MSCs in the development of altered CMFs. This dissertation research has found that differentially expressed PD-L1, but not PD-L2, alters T cell proliferation and type 1 immune responses. IBD-derived colonic MSCs have altered stemness properties compared to multipotent cells isolated from the normal colon and human bone marrow. Furthermore, MSCs are sensitive to the IBD inflammatory milieu, and I observed that this sensitivity resulted in the altered expression on stemness potency factors, and differential expression of PD-L1 similar to that of IBD-CMFs. The data in this dissertation strongly suggests that altered PD-L1 expression by IBD-CMFs is likely to contribute to the inflammatory immune responses in IBD, and that alteration of MSCs by the IBD inflammatory milieu may contribute to the differential expression of PD-L1 in CMFs. Further, the changes in IBD-MSCs and of normal MSCs exposed to the IBD inflammatory milieu demonstrated here have significant implications for the use of normal MSC in stem cell therapy for IBD patients.

Inflammation, IBD, stem cells, mesenchymal stem cells, Crohn's, Ulcerative Colitis, colitis, CD, UC, Inflammatory Bowel Disease