Fibroblast Homeostasis and their Contributions to Intestinal Polyp Formation

Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics

First Advisor

Sumigray, Kaelyn

Abstract

Fibroblasts function as a critical niche component to regulate epithelial homeostasis through mechanics and signaling. However, the regulatory principles governing fibroblast homeostasis are largely unknown. Fibroblast dysregulation has emerged as a pathological contributor in epithelial diseases such as intestinal polyposis. Here, using an inducible Bmp-loss-of-function polyposis model, we define stepwise mechanisms unraveling how dysregulated signaling perturbs fibroblast dynamics, which in turn, disrupt their function to regulate epithelial homeostasis. Intriguingly, the first initiating event leading to epithelial polyps was architectural and impacted the fibroblasts, not the epithelium. Bmp signaling inhibition induced fibroblast hypercontractility, which then led to tissue-scale coordinated movements, turning fibroblast organization from an elaborate network into collapsed clusters. Subsequently, epithelium became hyperproliferative in polyps. Using in vitro models, we show that fibroblast hypercontractility not only disrupted their network organization, but also enhanced their ability to support epithelial growth, leading to epithelial dysregulation. Overall, our studies reveal fibroblast mechanics as a key regulator of niche architecture and epithelial proliferation to maintain tissue homeostasis, with its disruption leading to epithelial diseases.

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