Project description
Dynamic tissue response to injury
Tissue regeneration and repair is driven by a small subpopulation of resident stem cells. However, in the colon, mucosal injury appears to cause differentiated cells to revert back to a stem cell phenotype. Although remarkable, this phenomenon may be associated with a higher risk of mutagenesis as differentiated cells may have acquired genetic and epigenetic alterations or be the cause for increased exposure to pathogenic microbiota. Funded by the European Research Council, the REVERT project aims to investigate how tissues respond to injuries. Using cell lineage tracing experiments, researchers will provide fundamental insight into the molecular players responsible for mucosal integrity and decipher the regenerative mechanisms in response to injury.
Objective
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.
Fields of science
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
10117 Berlin
Germany