The Warburg effect is necessary to promote glycosylation in the blastema during zebrafish tail regeneration

作者：Jason Sinclair, David R. Hoying, Erica Bresciani, Damian Dalle Nogare, Carli D. Needle, Alexandra Berger, Weiwei Wu, Kevin Bishop, Abdel Elkahloun, Ajay Chitnis, Paul Liu, Shawn M. Burgess · 发表于：npj Regenerative Medicine · 年份：2021 · DOI：10.1038/s41536-021-00163-x · 被引用次数：58 · 研究领域：Proteoglycans and glycosaminoglycans research、Zebrafish Biomedical Research Applications、Developmental Biology and Gene Regulation

Throughout their lifetime, fish maintain a high capacity for regenerating complex tissues after injury. We utilized a larval tail regeneration assay in the zebrafish Danio rerio, which serves as an ideal model of appendage regeneration due to its easy manipulation, relatively simple mixture of cell types, and superior imaging properties. Regeneration of the embryonic zebrafish tail requires development of a blastema, a mass of dedifferentiated cells capable of replacing lost tissue, a crucial step in all known examples of appendage regeneration. Using this model, we show that tail amputation triggers an obligate metabolic shift to promote glucose metabolism during early regeneration similar to the Warburg effect observed in tumor forming cells. Inhibition of glucose metabolism did not affect the overall health of the embryo but completely blocked the tail from regenerating after amputation due to the failure to form a functional blastema. We performed a time series of single-cell RNA sequencing on regenerating tails with and without inhibition of glucose metabolism. We demonstrated that metabolic reprogramming is required for sustained TGF-β signaling and blocking glucose metabolism largely mimicked inhibition of TGF-β receptors, both resulting in an aberrant blastema. Finally, we showed using genetic ablation of three possible metabolic pathways for glucose, that metabolic reprogramming is required to provide glucose specifically to the hexosamine biosynthetic pathway while ...