Mechanical regulation of the intestinal stem cell niche in development and disease

Tissue turnover and regeneration are orchestrated by stem cells that both differentiate and self-renew. The balance between self-renewal, proliferation, and commitment depends on the stem cell microenvironment, or “niche”. Importantly, stem cells are not simply passive responders to their niches; instead, they play an integral role in building and communicating with their immediate microenvironment. Although multiple studies have described the molecular and cellular composition of the niche to date, it is still unclear if and how the mechanical properties of the microenvironment regulate stem cell emergence and maintenance. This research project investigates the intricate dynamics between mechanical cues, the stromal niche, and stem cell behavior within the context of intestinal development, pathology, and tumorigenesis. Using multidisciplinary methodologies, this study aims to uncover how the mechanical microenvironment influences the emergence of intestinal stem cells (ISCs) during development, with a focus on substrate stiffness, tension, compression and topology. Additionally, the research delves into the role of the stromal niche in Necrotizing Enterocolitis (NEC), a severe inflammatory disorder in preterm infants, seeking to elucidate altered stromal-ISC interactions that could contribute to the physiopathology of the disease. Finally, the project also explores the mechano-sensing function of PIEZO channels in colorectal tumorigenesis, investigating their impact on cancer stem cell properties and downstream signaling pathways.