Aldh2 dependent formaldehyde metabolism fuels purine demands in melanocyte stem cells

Aldehyde-processing enzymes are viewed as essential clearing agents that rapidly deactivate harmful aldehydes. In the bone marrow, two specific enzymes, aldehyde dehydrogenase (ALDH) 2 and alcohol dehydrogenase (ADH) 5, were previously reported to protect hematopoietic stem cells from endogenous formaldehyde accumulation. Unexpectedly, we found that melanocyte stem cells (McSCs) in zebrafish depend on formate, an Aldh2-generated reaction product, to drive regeneration. Activated McSCs require Aldh2 (but not Adh5) to generate differentiated progeny, and by using scRNA-sequencing analysis, we identified a de novo purine biosynthesis program that is uniquely present in activated McSCs. Consistent with formate serving as one-carbon units for nucleotide biosynthesis, we found that purine supplementation (but not pyrimidine supplementation) was able to restore melanocyte regeneration in the absence of Aldh2. This work shows that Aldh2 enzymes generate reaction products that are needed to meet metabolic demands in regeneration.