Acid sphingomyelinase is a gatekeeper of placental labyrinthine architecture and function.

Sphingolipids are a class of bioactive signaling lipids that regulate an array of fundamental cellular processes, including cell survival, proliferation, and differentiation. Deficiency of acid sphingomyelinase-an enzyme of the sphingolipid metabolic pathway- has been previously implicated in human placental pathologies. We demonstrate that acid sphingomyelinase (Smpd1) is required for normal placental development in mouse, and its deficiency results in an intrauterine growth restriction phenotype. Smpd1-deficient placentas display several anatomical abnormalities, including reduced labyrinth compartment and increased fetal-maternal interhaemal distance. Finally, we observed several hallmarks of defective autophagy and lysosomal impairment in Smpd1-/- placentas, which could explain the inability of Smpd1-/- trophoblast to respond to nutrient starvation. Fetal growth restriction could not be rescued by transfer of Smpd1 deficient embryos into a wildtype uterine environment, however, restoration of transcription factor EB (TFEB) phosphorylation was detected. Thus, we conclude that due to a smaller labyrinthine area Smpd1 deficiency leads to a decrease in exchange between maternal and fetal blood space, limiting the supply of nutrients to the fetus, resulting in growth restriction.