Dynamics of the Mammalian Placental Metabolome in Placentogenesis and Embryonic Development

Mammalian placental metabolism is crucial for both placental and embryonic development. However, the metabolic profiles of placentas and their regulatory roles in placentogenesis and embryonic development at different developmental stages remain poorly characterized. To address these questions, we collect 501 mouse placentas spanning embryonic day (E) 8.5-14.5 and construct metabolomic-transcriptomic atlases of placentogenesis. Metabolomic and transcriptomic analyses reveal that placental samples from E8.5 to E14.5 are clustered into three separated states: E8.5, E9.5-10.5, and E11.5-14.5, pinpointing the metabolic transitions during placentogenesis from E8.5 to E9.5 and from E10.5 to E11.5. Based on a series of metabolite and enrichment analyses, Nicotinamide adenine dinucleotide (NAD(H)), flavin adenine dinucleotide (FAD), and L-glutamate (Glu) are identified as differentially abundant metabolites (DAMs) during E8.5-14.5. Using in vitro cultured (IVC) embryos, NAD(H) is shown to promote the extension of embryonic body length, through accelerated segmentation and increased proliferation, as verified in NAD(H)-treated mouse embryonic stem cell (mESC)-induced presomitic mesoderm (PSM)-like progenitor cells. These findings not only serve as an invaluable resource for understanding placental metabolism and its contribution to embryogenesis but also shed light on the mechanisms underlying developmental abnormalities associated with placental metabolic dysfunction.