Perish in the Attempt: Regulated Cell Death in Regenerative and Nonregenerative Tissue.

Significance: A cell plays its roles throughout its life span, even during its demise. Regulated cell death (RCD) is one of the key topics in modern biomedical studies. It is considered the main approach for removing stressed and/or damaged cells. Research during the past two decades revealed more roles of RCD, such as coordinating tissue development and driving compensatory proliferation during tissue repair. Recent Advances: Compensatory proliferation, initially identified in primitive organisms during the regeneration of lost tissue, is an evolutionarily conserved process that also functions in mammals. Among various types of RCD, apoptosis is considered the top candidate to induce compensatory proliferation in damaged tissue. Critical Issues: The roles of apoptosis in the recovery of nonregenerative tissue are still vague. The roles of other types of RCD, such as necroptosis and ferroptosis, have not been well characterized in the context of tissue regeneration. Future Directions: In this review article, we attempt to summarize the recent insights on the role of RCD in tissue repair. We focus on apoptosis, with expansion to ferroptosis and necroptosis, in primitive organisms with significant regenerative capacity as well as common mammalian research models. After gathering hints from regenerative tissue, in the second half of the review, we take a notoriously nonregenerative tissue, the myocardium, as an example to discuss the role of RCD in terminally differentiated quiescent cells. Antioxid. Redox Signal. 39, 1053-1069.