Mechanisms of intestinal epithelial regeneration post focal irradiation

Radiotherapy (RT) is a common treatment for abdominal cancers like pancreatic tumors. Despite advancements in RT delivery, its effectiveness is hindered by the proximity of the radiosensitive intestine.
To understand the intestinal epithelial regeneration and the molecular mechanisms of RT-induced toxicities, we developed a clinically relevant mouse model of focal RT, by implanting a radiopaque marker on the jejunum. We have previously shown that interleukin-6 is necessary for epithelial regeneration post focal irradiation. Intriguingly, we observed increased crypt length and stem cell proliferation at adjacent non-irradiated sites (wound edge). A dose escalation (up to 32 Gy) resulted in 100% survival for focally irradiated mice, while whole abdomen IR led to mortality within a week post-irradiation. This prompted us to delve deeper into understanding how stem cells from adjacent non-irradiated regions contribute to the regeneration of the radiation-damaged site. Through the use of single-cell RNA sequencing, spatial transcriptomics and genetically engineered mouse models, our goal is to unravel the mechanisms underlying intestinal regeneration. This research has the potential to enhance therapeutic outcomes and improve the quality of life for patients.