Stromal cells are abundant in the intestinal wall and together with the extracellular matrix constitute the connective tissue of the gut. Besides their structural role there are accumulating evidence that stromal cells participate in host defense, autoimmune intestinal inflammation, epithelial reinstitution, wound healing and the maintenance of intestinal homeostasis. In contrast to the few stromal subsets previously identified by surface expression markers, functional genomics have revealed significant diversity of intestinal stromal cells indicating multiple roles in intestinal homeostasis. Different subpopulations of mesenchymal cells have been identified to support epithelial crypt stem cell maintenance and function via Wnt and BMP signaling. Other subsets, through a variety of surface receptors, respond to DAMPs, PAMPs and cytokines by producing chemokine gradients that protect the host against enteric pathogens or perpetuate intestinal inflammation. During chronic intestinal inflammation stromal cells respond to the local cytokine milieu in cooperation with extracellular matrix components to regulate the functions of the epithelial barrier, the immunological response, the process of wound healing or to induce intestinal fibrosis.
Intestinal fibrosis pathways induced by the extensive cross-talk of immune cells acting as the stimuli and stromal cells acting as the extracellular matrix producers are especially relevant in Inflammatory Bowel Disease (IBD). Fibrosis is the end result of failure of intestinal remodeling during sustained inflammation that drives ECM overproduction by stromal cells and leads to structuring disease sub-phenotypes with compromised intestinal function. Despite advances in stromal cell function and pathophysiology the core-communication pathways between immune and stromal cells leading to perpetuation of inflammation and remodeling failure have not been clearly identified. The role of stromal cells in epithelial reinstitution during chronic intestinal inflammation is also understudied. Exploration and prioritization of post-inflammatory fibrotic pathways and identification of regeneration strategies is an absolute prerequisite in order to prevent or reverse intestinal fibrosis and restore intestinal function in IBD.
1. Stromal cell role in the physiology of mucosal immune system and mechanisms of action
2. Stromal cell contribution in the maintenance of intestinal stem cells, epithelial reinstitution and wound healing
3. Stromal cell interactions with commensal and pathogenic intestinal microflora in intestinal homeostasis or dysbiosis
4. Diversity, molecular signatures and function of intestinal stromal cells in acute infectious and chronic autoimmune intestinal inflammation including Ulcerative colitis and Crohn’s disease (IBDs)
5. The role of intestinal stroma in post-inflammatory intestinal fibrosis
6. Prediction of treatment responses in IBD by the intestinal mesenchymal molecular profile, role as a biomarker
7. Preclinical or clinical studies on strategies that modify IBD treatment responses through manipulation of stromal cell function
8. Use of genetically modified stromal cells in organoid development for modeling and regeneration strategies for treating IBD and intestinal fibrosis.
Stromal cells are abundant in the intestinal wall and together with the extracellular matrix constitute the connective tissue of the gut. Besides their structural role there are accumulating evidence that stromal cells participate in host defense, autoimmune intestinal inflammation, epithelial reinstitution, wound healing and the maintenance of intestinal homeostasis. In contrast to the few stromal subsets previously identified by surface expression markers, functional genomics have revealed significant diversity of intestinal stromal cells indicating multiple roles in intestinal homeostasis. Different subpopulations of mesenchymal cells have been identified to support epithelial crypt stem cell maintenance and function via Wnt and BMP signaling. Other subsets, through a variety of surface receptors, respond to DAMPs, PAMPs and cytokines by producing chemokine gradients that protect the host against enteric pathogens or perpetuate intestinal inflammation. During chronic intestinal inflammation stromal cells respond to the local cytokine milieu in cooperation with extracellular matrix components to regulate the functions of the epithelial barrier, the immunological response, the process of wound healing or to induce intestinal fibrosis.
Intestinal fibrosis pathways induced by the extensive cross-talk of immune cells acting as the stimuli and stromal cells acting as the extracellular matrix producers are especially relevant in Inflammatory Bowel Disease (IBD). Fibrosis is the end result of failure of intestinal remodeling during sustained inflammation that drives ECM overproduction by stromal cells and leads to structuring disease sub-phenotypes with compromised intestinal function. Despite advances in stromal cell function and pathophysiology the core-communication pathways between immune and stromal cells leading to perpetuation of inflammation and remodeling failure have not been clearly identified. The role of stromal cells in epithelial reinstitution during chronic intestinal inflammation is also understudied. Exploration and prioritization of post-inflammatory fibrotic pathways and identification of regeneration strategies is an absolute prerequisite in order to prevent or reverse intestinal fibrosis and restore intestinal function in IBD.
1. Stromal cell role in the physiology of mucosal immune system and mechanisms of action
2. Stromal cell contribution in the maintenance of intestinal stem cells, epithelial reinstitution and wound healing
3. Stromal cell interactions with commensal and pathogenic intestinal microflora in intestinal homeostasis or dysbiosis
4. Diversity, molecular signatures and function of intestinal stromal cells in acute infectious and chronic autoimmune intestinal inflammation including Ulcerative colitis and Crohn’s disease (IBDs)
5. The role of intestinal stroma in post-inflammatory intestinal fibrosis
6. Prediction of treatment responses in IBD by the intestinal mesenchymal molecular profile, role as a biomarker
7. Preclinical or clinical studies on strategies that modify IBD treatment responses through manipulation of stromal cell function
8. Use of genetically modified stromal cells in organoid development for modeling and regeneration strategies for treating IBD and intestinal fibrosis.
