REVERT · REVERT Regeneration as a Vulnerable State for Microbe-Driven Injury and Tumorigenesis

Tissues with high turnover are hierarchically organized and rely on long-lived stem cells that are protected by a variety of mechanisms. In the gastrointestinal tract, highly active stem cells are located in the base of crypts, where differentiated cells shield them from environmental threats. It has recently emerged that mucosal injuries initiate regenerative repair programs that promote a disruption of cellular hierarchies and reversal of differentiated cells back to the proliferative stem cell state. While this remarkable plasticity enables rapid injury repair, I propose that the recruitment of differentiated cells to the stem cell pool represents a critical event for the accumulation of genetic and epigenetic alterations because differentiated cells are more exposed to the environment and less equipped to repair DNA damage. Particularly in the colon with its dense and potentially harmful microbiota, injury-driven de-differentiation may be linked to loss of cell functions that control the microbiota and direct exposure of “de novo stem cells” to bacteria and their genotoxic virulence factors. REVERT will investigate the long-term consequences of such transient interactions on molecular, cellular, and tissue levels and explore the impact of the regenerative state on mucosal microbial ecology and function. REVERT will combine stem cell biology approaches such as, lineage tracing, organoids, and assembloids with microbiology techniques such as gnotobiotic infection models, and integrate complex systems biology technologies to build up a picture of dynamic tissue responses to injuries and the ability of microbes to interfere with them. REVERT has the potential to establish fundamental new knowledge of principles that govern mucosal integrity and reveal its vulnerabilities in the context of injury. It has the potential to drastically expand our understanding of processes that drive chronic tissue dysfunction and carcinogenesis.