Apoptosis-resistant cells drive compensatory proliferation via cell-autonomous and non-autonomous functions of the initiator caspase Dronc.

Caspases are best known for promoting apoptosis, yet their role in tissue regeneration by compensatory proliferation remains unclear. Using Drosophila wing discs and a delayed reporter for the initiator caspase-9 ortholog Dronc activity, we identify two apoptosis-resistant epithelial cell populations that mediate regeneration after ionizing radiation: Dronc-activating (DARE) and non-activating (NARE) cells. Dronc activity in DARE cells, independent of Dark and effector caspases, drives regeneration both cell-autonomously and non-cell-autonomously. The TNFR in DARE cells, Wengen, likely activated by ROS, strongly promotes DARE proliferation, while TNF/Eiger and TNFR Grindelwald moderately suppress it. Downstream, p38 MAPK is the main signaling essential for DARE and NARE cell proliferation. Myo1D ensures DARE survival by preventing lethal effector caspase activation, whereas Myo7A/Crinkled supports moderate caspase activity. Dying cells trigger DARE induction, and both DARE and NARE transmit apoptosis resistance to progeny, with DARE progeny showing enhanced resistance. Maintaining balanced DARE-NARE proliferation is crucial for proper regeneration, growth, and differentiation, insights that may be relevant to radiation-resistant cells in cancer therapy.