Intestinal fibroblasts in inflammation and cancer

The mature intestine is a complex organ responsible for the uptake of nutrients and bile secretion, whilst acting tolerant of commensal bacteria but protective against invading
pathogens. The innermost layer of the intestinal wall, the epithelium, consists of a monolayer of cells that carry the unique property of self-renewal. This process is driven by intestinal stem cells that give rise to daughter cells that eventually specialize into exclusive cell types (differentiation). A perfect balance between epithelial proliferation and differentiation is often referred to as intestinal homeostasis. One of the most important signaling pathways that orchestrates intestinal homeostasis is the Hedgehog pathway. In order for this pathway to function, it requires tight interactions between the epithelium and the underlying compartment where specific cells reside; fibroblasts. Fibroblasts provide structure and stability but also play instrumental roles in disease. This thesis focuses on the importance of intestinal fibroblasts, in the context of inflammation and cancer. We show that the Hedgehog pathway signals from the intestinal epithelium to fibroblasts specifically. Via these signals it suppresses the earliest stages of colorectal cancer, but also a severe inflammatory response. We suggest a key role for the chemokine CXCL12 in Hedgehog-driven inflammation and for intestinal wound healing in general. Furthermore, we identify CD90 as a marker for fibroblasts that surround stem cells and provide support through the expression of the growth factors class 3 semaphorins. The results from this thesis provide a valuable addition to the exciting evidence that intestinal fibroblasts fulfil crucial roles in intestinal immunity, cancer development and stem cell maintenance, directed by important signaling pathways such as the Hedgehog pathway.