Decoding human placental cellular and molecular responses to maternal obesity and fetal growth

Obesity poses risks to maternal health and increases the likelihood of short– and long-term adverse pregnancy outcomes in the offspring. The placenta, a key organ at the maternal-fetal interface, responds to maternal obesity and regulates fetal growth. To investigate the molecular features of physiological adaptation, we perform single-nuclei RNA-seq on human placentas and compared the transcriptomic profiles of women with obesity delivering appropriate-or large-for-gestational age (i.e., AGA and LGA) babies with those from normal-weight healthy controls delivering AGA babies. Commonness-score metric is developed to identify responses attributable to maternal obesity effects or fetal growth. We find hypoxia and induction of TNF-α signaling in syncytiotrophoblasts, while the receptor tyrosine kinases are down-regulated in cytotrophoblasts in maternal obesity irrespective of fetal growth. Notably, we identify that the fine-tune of PI3K-AKT and MAPK cascade signaling pathways in cytotrophoblasts underlies AGA versus LGA. Hofbauer cells upregulate immunometabolic genes specifically in LGA outcomes and also express most of the ligands detected only in placentas of LGA. Finally, we also use a novel microfluidic organs-on-a-chip device fabricated for co-culturing adipose spheroids and trophoblast organoids. This system recapitulates some responses of syncytiotrophoblasts to maternal obesity, offering a functionally relevant reductionistic system to study maternal-placental interaction. Our findings deconvolute key cellular and molecular adaptation of the placenta to maternal obesity and fetal overgrowth in physiological condition.