Lactate shuttle between cytotrophoblast and syncytiotrophoblast in the placenta enhances ferroptosis resistance and maintains placental homeostasis: implications for early pregnancy loss.

backgroundThe placenta serves as the interface between the mother and fetus, playing a critical role in ensuring fetal development and maternal health during pregnancy in viviparous mammals. In human placental villi, the outermost multinucleated syncytiotrophoblast (STB) are formed through the syncytialization of inner layer mononucleated cytotrophoblasts (CTBs). Despite the high cellular homeostasis exhibited by STB, the underlying mechanisms remain poorly understood. Our recent investigation into the metabolic properties of human placental trophoblasts reveals significant metabolic rewiring during syncytialization. This leads us to hypothesize that lactate produced by CTBs may be actively transported to STB, potentially protecting polyunsaturated fatty acids (PUFA)-rich STB from excessive ferroptosis, thereby contributing to the maintenance of cellular homeostasis in STB.

methodsTo test this hypothesis, we conducted both in vitro and in vivo studies, utilizing clinical specimens from patients with recurrent pregnancy loss (RPL), primary cultured human CTBs and STB, induced syncytialization of trophoblast cell line BeWo, and a lipopolysaccharide (LPS)-induced mouse model of early pregnancy loss.

resultsOur data demonstrates that lactate primarily produced by CTBs can be transported to STB via monocarboxylate transporter 1 (MCT1)-mediated transport, activating the PI3K (phosphatidylinositol 3-kinase)-AKT (protein kinase B, PKB)-mTOR (mechanistic target of rapamycin) signaling pathway, and subsequently upregulating the expression of stearoyl-CoA desaturase-1 (SCD1) and glutathione peroxidase 4 (GPX4). This process mitigates lipid peroxidation and reduces ferroptosis susceptibility in STB. Administration of lactate in LPS-induced mice significantly mitigates placental ferroptosis and rescues fetal loss. Pathological analyses of the placentas from RPL (recurrent early pregnancy loss) patients demonstrates impaired lactate synthesis capacity and elevated ferroptosis biomarkers.

conclusionsThese findings elucidate the mechanism whereby lactate shuttle between trophoblast layers suppresses ferroptosis and maintains cellular homeostasis in the placenta. The results highlight the potential therapeutic utility of lactate for addressing severe pregnancy complications such as early pregnancy loss.