Understanding Necrosis-Induced Tissue Regeneration

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Project Summary Cell death has a critical role in human development and recovery following injury or disease. This is because dying cells produce signals that can significantly impact the behavior of the surrounding cells. The identity and consequences of these signals are diverse and context dependent, but many are known to regulate the survival, activity and proliferation of neighboring cells following injury. Thus, a better understanding of how dying cells impact surviving tissue could uncover novel therapeutic interventions to improve healing and regeneration following injury or disease. While this signaling phenomenon has been characterized in apoptotic cell death, it is unclear whether unregulated forms of cell death, such as necrosis, have a similar impact on tissue behavior and repair. Necrosis is the rapid, disordered death of cells, which can occur in any tissue and is central to many human conditions, including traumatic injuries (burns, frostbite), infections, and ischemic injuries like strokes and heart attacks. Several factors released from necrotic cells have been identified, however, the identity of other signals and whether they influence recovery has yet to be examined. The aim of this proposal is to investigate how necrotic wounds impact surrounding tissues to influence recovery and regeneration. Evidence that signals from dying cells impact nearby tissues first originated from studies of the larval wing primordia in Drosophila, called imaginal discs. These tissues have significant regenerative capacity, the study of which has led to important insights into the genetic events necessary for damage-induced tissue recovery. However, most of these studies examine apoptosis-induced regeneration, limiting our understanding of how cell death impacts surviving tissue to this type of injuries. To overcome this limitation, we have established a genetic tool that allows us to trigger either necrosis or apoptosis in the developing wing disc, and to genetically manipulate the surrounding cells that respond to each type of damage. With this tool we found that discs successfully regenerate in each case, but via different mechanisms. Notably, necrosis leads to widespread apoptotic cell death at a distance from the wound. This necrosis- induced apoptosis, or NiA, is necessary to drive regenerative proliferation and is therefore critical for proper recovery. The cause of NiA and how it promotes regeneration are currently unknown. Here, we propose to characterize the genetic response that leads to successful regeneration following necrosis focusing on the role of NiA. Our work aims to identifying how necrosis leads to NiA, understand how NiA promotes regeneration, and comprehensively characterize the necrosis-induced regeneration program that results in NiA using whole genome sequencing approaches. Together, the results of these experiments will contribute to our fundamental understanding of tissue repair in response to necrosis, which is ultimately essential for developing novel therapeutic approaches to treat necrotic wounds and promote regeneration in humans.