Qian, Q.; Nagai, H.; Sanaki, Y.; Hayashi, M.; Kimura, K.; Nakajima, Y.-i.; Niwa, R.

Cellular plasticity, the ability of a differentiated cell to adopt another phenotypic identity, is restricted under basal conditions, but can be elicited upon damage to facilitate regeneration. Such damage-induced cellular plasticity restores homeostasis and prevents pathology, yet its underlying molecular basis remains largely unexplored. Here, we reported damage-induced cellular plasticity of secretory enteroendocrine cells (EEs) in the adult Drosophila midgut. We found that ionizing radiation enhanced EE plasticity such that it promoted EEs to dedifferentiate into ISCs and subsequently re-differentiate towards ECs. We identified that radiation induced the production of a stress-inducible transcription factor Xrp1 in EE lineages, and its upregulation was necessary for EE plasticity. Single-cell RNA sequencing of guts with EE-specific Xrp1 overexpression revealed ectopic expression of progenitor-specific genes in EEs, which was necessary for Xrp1 to drive EE plasticity. Our work provides a mechanistic framework for understanding cellular plasticity and suggests its potential role in damage-induced responses.