Regeneration is triggered by cells dying due to various types of injuries. However, it remains unclear whether different types of cell death elicit distinct regeneration responses. Here, we systematically profile dynamic transcriptional responses of macrophages and lateral line cells to different cell death modalities during zebrafish sensory hair cell regeneration. We show that chemogenetically induced programmed hair cell death triggers a diminished inflammatory response compared to pharmacologically induced cell lysis, characterized by minimal neutrophil recruitment, distinct transcriptional profiles in phagocytosing macrophages and reduced expression of injury-responsive genes in lateral line cells. Nevertheless, regeneration ultimately converges on a shared set of regeneration-specific genes. Importantly, preventing immune cell recruitment enhances injury-induced support cell proliferation in response to programmed, but not unprogrammed cell death, highlighting cell death-dependent regenerative outcomes following immune cell inhibition. Our findings demonstrate that different forms of cell death trigger distinct molecular events, with implications for tailoring regenerative therapies to specific injury contexts. How different types of cell death influence cellular regeneration is unclear. Here, the authors profile transcriptional immune and support cell injury responses to different hair cell death modalities using scRNA-seq. Notably, blocking immune cells differentially affects regenerative outcomes depending on the cell death context.
Münch et al. (Thu,) studied this question.