Triglycerides are an essential fuel reserve for gap-junction dynamics during epithelial regeneration
July 2
Proper fuelling of regenerating epithelia is critical to sustain morphogenetic progression, but the contribution of fatty-acid (FA) combustion to this process has remained obscure. Here we show that acute inhibition of an epithelium-enriched triglyceride lipase, DDHD2 (a genetic driver of defective limb regeneration), or of the mitochondrial lipid carrier CPT1 provokes rapid arrest of digit-tip regrowth in adult mice. These findings indicate that, in vivo, proliferative epithelial cells continuously channel FAs liberated from intracellular lipid droplets (LDs) through β-oxidation to support regenerative bioenergetics. In isolated blastemal cultures, suppression of gap-junction signalling or pharmacological blockade of DDHD2 causes marked accumulation of LDs, including at leading-edge membranes, and FAs released from peripheral LDs enter mitochondria in a signalling-dependent manner to fuel compartmentalised ATP synthesis. Together, these data demonstrate that morphogenetically active cell fronts exploit LDs during patterning cues to secure local metabolic support and are likely essential for successful tissue regeneration in vivo.