A regeneration-triggered metabolic adaptation is necessary for cell identity transitions and cell cycle re-entry to support blastema formation and bone regeneration

Abstract

Regeneration depends on the ability of mature cells at the injury site to respond to injury, generating tissue-specific progenitors that incorporate the blastema and proliferate to reconstitute the original organ architecture. The metabolic microenvironment has been tightly connected to cell function and identity during development and tumorigenesis. Yet, the link between metabolism and cell identity at the mechanistic level in a regenerative context remains unclear. The adult zebrafish caudal fin, and bone cells specifically, have been crucial for the understanding of mature cell contribution to tissue regeneration. Here, we use this model to explore the relevance of glucose metabolism for the cell fate transitions preceding new osteoblast formation and blastema assembly. We show that injury triggers a modulation in the metabolic profile at early stages of regeneration to enhance glycolysis at the expense of mitochondrial oxidation. This metabolic adaptation mediates transcriptional changes that make mature osteoblast amenable to be reprogramed into pre-osteoblasts and induces cell cycle re-entry and progression. Manipulation of the metabolic profile led to severe reduction of the pre-osteoblast pool, diminishing their capacity to generate new osteoblasts, and to a complete abrogation of blastema formation. Overall, our data indicate that metabolic alterations have a powerful instructive role in regulating genetic programs that dictate fate decisions and stimulate proliferation, thereby providing a deeper understanding on the mechanisms regulating blastema formation and bone regeneration.

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

“…Intriguingly, recent findings suggest that a similar metabolic switch also occurs following adult fin regeneration in zebrafish, and inhibition of this switch results in failure in blastema formation in the adult fin as well. 46 Thus, our work suggests that aerobic glycolysis is important at two distinct points following injury: the first being within minutes following injury, during the rapid wound healing phase and the second during the tail regeneration phase. Though a blastema is typically highly proliferative, there is an absence of raised lactate levels in any region aside from the notochord bead during the proliferative phase of fin and tail regeneration.…”

“…It is unclear at this point if this different reliance on aerobic glycolysis between the two amputation models reflects diversity in the constituent cell types being regenerated or the differing anabolic needs for regeneration of the fin fold, versus overall regeneration of many tissue types. Intriguingly, recent findings suggest that a similar metabolic switch also occurs following adult fin regeneration in zebrafish, and inhibition of this switch results in failure in blastema formation in the adult fin as well 46 …”

“…Intriguingly, recent findings suggest that a similar metabolic switch also occurs following adult fin regeneration in zebrafish, and inhibition of this switch results in failure in blastema formation in the adult fin as well. 46 …”

Glycometabolic reprogramming in cementoblasts: A vital target for enhancing cell mineralization

“…Metabolic alterations play a significant instructional function in controlling genetic programs that determine fate decisions and accelerate proliferation, thereby enhancing our knowledge of the mechanisms governing bone regeneration. 60 Researches find that the genes related to glycolysis, including GLUT1 and PDK1, are important in osteoblast differentiation. 61,62 Succinate supplementation boosted hPDLC proliferation, migration, and osteogenesis with increased hexokinase 2 (HK2) and PFKFB3.…”

“…For the exploration of the molecular mechanism, we probed the role of LDHA in cementoblast mineralization. Metabolic alterations play a significant instructional function in controlling genetic programs that determine fate decisions and accelerate proliferation, thereby enhancing our knowledge of the mechanisms governing bone regeneration 60 . Researches find that the genes related to glycolysis, including GLUT1 and PDK1, are important in osteoblast differentiation 61,62 .…”