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

## TL;DR

This study uses RNA sequencing to explore how obesity and fetal growth affect placental cells, revealing distinct molecular responses linked to inflammation and metabolism.

## Contribution

The study identifies cell-type-specific gene expression patterns in placentas from obese mothers, distinguishing shared and LGA-specific responses.

## Key findings

- Syncytiotrophoblasts in obese mothers show upregulated hypoxia and TNF-α signaling.
- Hofbauer cells in LGA placentas exhibit altered immunometabolism and elevated SPP1 expression.
- A microfluidic co-culture system models syncytiotrophoblast responses to adipose tissue.

## 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.

Women with obesity often deliver large‐for‐gestational‐age (LGA) infants. Single‐nucleus RNA sequencing of term placenta reveals that hypoxia and TNF‐α signaling in syncytiotrophoblasts are featured in maternal obesity, but inflammatory signatures in Hofbauer cells and response to lipid or carbohydrate metabolism in fibroblasts are specific to LGA. A microfluidic co‐culture models trophoblast responses to adipose tissue providing a minimalistic approach to study the maternal obesity on placentas.