# Distinct transcriptional and epigenomic programs define Hofbauer cells in term placenta

## TL;DR

This study identifies unique gene and chromatin patterns in Hofbauer cells, revealing their specialized role in placental function and adaptability.

## Contribution

The study reveals a novel transcriptional network involving NR4A1–3, glucocorticoid receptor, and RFX family shaping Hofbauer cell identity.

## Key findings

- Hofbauer cells have distinct transcriptomic and chromatin accessibility profiles compared to other macrophages.
- A transcriptional network involving NR4A1–3, glucocorticoid receptor, and RFX family regulates lipid metabolism and angiogenesis in Hofbauer cells.
- Hofbauer cells show increased transcriptional activity and lipid transporter CD36 induction in response to IL-4 and rosiglitazone treatment.

## Abstract

Hofbauer cells (HBCs) are fetal macrophages located in the placenta that contribute to antimicrobial defense, angiogenesis, tissue remodeling, and metabolic processes within the chorionic villi. Although their roles in placental biology are increasingly recognized, the mechanisms that regulate HBC identity and function are not yet fully defined. This study aimed to define the core transcriptomic and epigenomic features of HBCs in term placentas and to examine their capacity for transcriptional responsiveness and phenotypic variation. Using chromatin accessibility profiling and bulk RNA-seq, we found that HBCs exhibit a unique gene expression and chromatin accessibility profile compared with other fetal and adult macrophages. We identified a coordinated transcriptional network involving nuclear receptors (NRs) NR4A1–3, the glucocorticoid receptor, and RFX family members (RFX1, RFX2, RFX5) that appears to shape HBC identity, particularly through pathways linked to lipid metabolism and angiogenesis. Although exploratory in nature, in vitro stimulation studies showed that HBCs exhibited increased transcriptional activity in response to combined IL-4 and rosiglitazone treatment, including induction of the lipid transporter CD36. Mass cytometry analysis revealed surface markers indicative of both immature and mature macrophage states. These results together indicate that HBCs are a distinct and diverse population of macrophages with a specialized, adaptable regulatory program in the human placenta.

Our study defines unique regulatory programs of placental Hofbauer cells, advancing understanding of their role in pregnancy health and potential disease.