Flavins in Focus: Vitamin B 2 as a Metabolic Keystone for Neuronal Repair in Regenerating Planarians

Abstract Regeneration imposes substantial metabolic demands to support the reconstruction of functional tissues. Essential vitamins are indispensable metabolic cofactors, yet whether their availability is spatially organized to support local metabolic demands within regenerative tissues remains largely unknown. Here, we identify previously undescribed flavin-rich cells, referred to as “flavinocytes”, that form an extensive network that spatially organizes vitamin B 2 metabolism in the planarian Schmidtea mediterranea . Using endogenous flavin autofluorescence as a label-free in vivo metabolic readout, we show that this network consists of elongated cells that form longitudinal varicosity-containing strands closely associated with the central nervous system. RNAi-mediated disruption of riboflavin uptake and metabolism reduced flavin-associated autofluorescence and its spatial distribution within the animal, while affecting blastema formation, eye regeneration, and nervous system reconstruction. These findings demonstrate that riboflavin metabolism is required for successful regeneration. Single-cell transcriptomics, protein localization, and functional perturbations further suggest a reciprocal relationship between flavinocytes and the regenerating nervous system, pointing to coordinated neuro-metabolic interactions during tissue repair. Together, our findings demonstrate the importance of riboflavin metabolism for nervous system regeneration and provide new insight into the spatial organization of metabolism during tissue regeneration.