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

ABSTRACT 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.