Decoding Human Placental Cellular and Molecular Responses to Obesity and Fetal Growth.

Maternal obesity increases the risks of large-for-gestational-age (LGA) births and subsequent cardiometabolic disorders in offspring. To identify placental signatures associated with these outcomes, we performed single-nucleus RNA sequencing on placentas from women with obesity delivering appropriate-for-gestational-age or LGA infants, compared to normal-weight controls. In maternal obesity, regardless of fetal growth, syncytiotrophoblasts showed upregulated hypoxia and TNF-α signaling, while cytotrophoblasts exhibited downregulated receptor tyrosine kinase signaling. However, villous non-trophoblasts displayed upregulated TNF-α signaling and inflammatory responses only in LGA placentas. Notably, Hofbauer cells in LGA placentas presented transcriptional alterations in immunometabolism-related genes and displayed elevated SPP1 expression, which potentially acts as a ligand for other placental cell types. We modeled key aspects of syncytiotrophoblast responses to adipose tissue using a customized microfluidic organoids-on-a-chip co-culture system. These findings revealed gene expression patterns of placental cells to maternal obesity that are shared or different between O-A and O-L, highlighting pathways for future mechanistic investigation.