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Resource and Technical AdvanceIn-Press PreviewImmunologyReproductive biology Open Access | 10.1172/jci.insight.195801

Distinct transcriptional and epigenomic programs define Hofbauer cells in term placenta

Benjámin R. Baráth,1 Dóra Bojcsuk,1 Krisztian Bene,1 Noemí Caballero-Sánchez,1 Tímea Cseh,1 João CR. de Freitas,2 Petros Tzerpos,1 Marta Toth,3 Zhonghua Tang,4 Seth Guller,4 Zoárd Tibor Krasznai,5 Patrícia Neuperger,6 Gabor J. Szebeni,7 Gergely Nagy,1 Tamás Deli,5 and Laszlo Nagy8

1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Baráth, B. in: PubMed | Google Scholar

1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Bojcsuk, D. in: PubMed | Google Scholar |

1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Toth, M. in: PubMed | Google Scholar

1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Tang, Z. in: PubMed | Google Scholar

1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Guller, S. in: PubMed | Google Scholar

1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Krasznai, Z. in: PubMed | Google Scholar

1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Neuperger, P. in: PubMed | Google Scholar

1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Szebeni, G. in: PubMed | Google Scholar

1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Nagy, G. in: PubMed | Google Scholar

1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Deli, T. in: PubMed | Google Scholar

1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

2Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, United States of America

3Department of Immunology, University of Debrecen, Debrecen, Hungary

4Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, United States of America

5Department of Obstetrics and Gynecology, University of Debrecen, Debrecen, Hungary

6Laboratory of Functional Genomics, HUN-REN Biological Research Centre, Szeged, Hungary

7Laboratory of Functional Genomics, HUN-REN Biological Reseach Centre, Szeged, Hungary

8Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeut, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Nagy, L. in: PubMed | Google Scholar |

Published December 23, 2025 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.195801.
Copyright © 2025, Baráth et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 23, 2025 - Version history
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Abstract

Hofbauer cells (HBC) are fetal-derived 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 sequencing, we found that HBCs exhibit a unique gene expression and chromatin accessibility profile compared to other fetal and adult macrophages. We identified a coordinated transcriptional network involving nuclear receptors NR4A1–3, the glucocorticoid receptor (GR), 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 RSG treatment, including induction of the lipid transporter CD36. Mass cytometry analysis revealed surface markers indicative of both immature and mature macrophage states. Together, these results indicated that HBCs represent a distinct and diverse macrophage population with specialized and adaptable regulatory program in the human placenta.

Graphical Abstract
graphical abstract
Supplemental material

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View Sample metadata including accession numbers and source references for transcriptomic datasets used in the study

View Tables generated during the process of RNA-seq data.

View Tables generated during the process of ATAC-seq data.

View qPCR results for the measured genes in HBC samples under control, IL-4, RSG, and combined IL-4/RSG treatment conditions with technical replicates.

Version history
  • Version 1 (December 23, 2025): In-Press Preview
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