Analyzing Wound Induced Polyploidy

Abstract

All organisms have developed strategies to respond to injury. Some tissues induce compensatory proliferation of surrounding cells which migrate into and invade the wound site. However, alternative strategies exist such as endoreplication, or repeated S-phase entry without mitosis, and syncytia formation by cell-cell fusion lead to the formation of polyploid cells that drive wound closure without proliferation. It was believed these alternative repair strategies were restricted to quiescent tissues. On the contrary, in this dissertation I have characterized that the mitotically capable Drosophila pupal notum induces both nuclear polyploidy and syncytia formation in response to wounding. I determined syncytia formed rapidly near wounds by both border breakdown and a novel temporally distinct shrinking cell behavior. Using sparsely labeled cells throughout the notum I was able to confirm cytoplasmic mixing between fusing cells and determined that half of the cells within 70 µm of the wound fused into syncytia. Syncytia then outcompeted unfused neighbors at the leading edge, such that the number of unfused cells at the leading edge always dropped to zero before wound closure. By fusing, syncytia rapidly relocalized resources from distal cells to the leading where they accumulated into large migratory structures, likely contributing to their invasiveness. Additionally, fusion at the leading edge reduced the need for coordinated border exchanges or intercalations at the leading edge likely increasing the rate of wound closure. These studies revealed wound induced polyploidy is not restricted to quiescent tissues and may be present in other mitotic tissues throughout the animal kingdom. Future studies to understand the induction and regulation of wound induced polyploidy will not only further our understanding of wound closure, but shed light on how polyploidy becomes dysregulated in pathological conditions like cancer.