A metabolic shift to glycolysis promotes zebrafish tail regeneration through TGF–β dependent dedifferentiation of notochord cells to form the blastema

Abstract

Mammals are generally poor at tissue regeneration, in contrast, fish maintain a high capacity for regenerating complex tissues after injury. Using larval zebrafish, we show that tail amputation triggers an metabolic shift to glycolysis in cells surrounding the notochord as they reposition to the amputation site. Blocking glycolysis prevents the fin from regenerating after amputation due to the failure to form a normal, pluripotent blastema. We performed a time series of scRNA-sequencing on regenerating tails under normal conditions or in the absence of glycolysis. Strikingly, we detected a transient cell population in the single cell analysis that represents notochord sheath cells undergoing a TGF-b dependent dedifferentiation and epithelium-to-mesenchyme transition to become pluripotent blastema cells. We further demonstrated that the metabolic switch to glycolysis is required for TGF-b signaling and blocking either glycolysis or TGF-b receptors results in aberrant blastema formation through the suppression of essential EMT mediators such as snai1.

Aerobic glycolysis is important for zebrafish larval wound closure and tail regeneration

“…Inhibition of glycolysis with 2DG resulted in a reduction of proliferating cardiomyocytes (Honkoop et al, 2019), indicating this metabolic switch to glycolysis is required for regrowth. Increased expression of glycolysis genes has also been suggested in zebrafish following larval tail amputation, with glycolysis inhibition resulting in abnormal blastema formation (Sinclair et al, 2020), and we additionally find that the glycolytic enzymes hexokinase and LDH are required for larval tail regeneration. Thus, aerobic glycolysis is required for successful regeneration through the formation or output of the notochord bead.…”

Intestine-enrichedapolipoprotein borthologs are required for stem cell differentiation and regeneration in planarians

“…Our RNA-Seq data suggest that transcription of regulators of amino acid metabolism, glycolysis, the tricarboxylic acid cycle, and other metabolic pathways respond to apob(RNAi), suggesting that planarian stem cell metabolism is just as dynamic as in other animals. The fact that apob(RNAi) seems to primarily affect post-mitotic states also suggests that planarian neoblasts might rely primarily on glycolysis for energy and metabolite supply, and shift to lipid metabolism and oxidative phosphorylation during differentiation, as in other systems [93][94][95] . Again, studies in animals with high regenerative capacity could generate greater insights into whether and how injury can induce metabolic switching.…”

Cardiac regenerative capacity: an evolutionary afterthought?

“…Therefore, heart regeneration, which depends on the ability of CMs to switch energy metabolism from a very efficient fatty acid oxidation to a more inefficient glucose metabolism by glycolysis and lactate fermentation, may have been a trade-off for an increase in energy demands in endotherms. This may not be restricted to only heart regeneration since a comparable metabolic switch towards glycolysis was also observed during appendage regeneration [147].…”