Molecular and cellular morphology of placenta unveils new mechanisms of reproductive immunology

Penghao Li; Liting Zeng; Xiaomiao Yan; Ziqi Zhu; Qiaoxiu Gu; Xuqing He; Sujuan Zhang; Rurong Mao; Jingliang Xu; Fengshan Xie; Hui Wang; Ziteng Li; Jing Shu; Weifeng Zhang; Yulin Sha; Jin Huang; Meng Su; Qu Zheng; Jian Ma; Xiaolin Zhou; Ming Li; Haiying Pan; Ya Li; Meiling Yan; Xueling Chen; Mingzhou Li; Keren Long; Fanli Kong; Chuang Tang; Ju Huang; Chanjuan Su; Jirui Li; Zheng Fang; Muwang Chen; Erpo Tian; Ying Zhong; Jiang Gu

doi:10.1016/j.jare.2025.01.025

Molecular and cellular morphology of placenta unveils new mechanisms of reproductive immunology

J Adv Res. 2025 Jan 20:S2090-1232(25)00044-X. doi: 10.1016/j.jare.2025.01.025. Online ahead of print.

Authors

Penghao Li¹, Liting Zeng², Xiaomiao Yan³, Ziqi Zhu⁴, Qiaoxiu Gu⁴, Xuqing He⁴, Sujuan Zhang⁵, Rurong Mao⁵, Jingliang Xu⁶, Fengshan Xie⁴, Hui Wang⁴, Ziteng Li⁴, Jing Shu⁵, Weifeng Zhang⁴, Yulin Sha⁵, Jin Huang⁴, Meng Su⁴, Qu Zheng⁵, Jian Ma⁵, Xiaolin Zhou⁵, Ming Li⁵, Haiying Pan⁵, Ya Li⁵, Meiling Yan⁵, Xueling Chen⁴, Mingzhou Li⁷, Keren Long⁷, Fanli Kong⁷, Chuang Tang⁷, Ju Huang⁸, Chanjuan Su⁴, Jirui Li⁴, Zheng Fang⁹, Muwang Chen⁹, Erpo Tian⁵, Ying Zhong⁵, Jiang Gu¹⁰

Affiliations

¹ Jinxin Research Institute for Reproductive Medicine and Genetics, Sichuan Jinxin Xi'nan Women's and Children's Hospital, Chengdu, China; Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, China.
² Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, China; Shenshan Medical Center, Memorial Hospital of Sun Yat-sen University, Shanwei 516600, China.
³ Jinxin Research Institute for Reproductive Medicine and Genetics, Sichuan Jinxin Xi'nan Women's and Children's Hospital, Chengdu, China; Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, China; Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China.
⁴ Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, China.
⁵ Jinxin Research Institute for Reproductive Medicine and Genetics, Sichuan Jinxin Xi'nan Women's and Children's Hospital, Chengdu, China.
⁶ Jinxin Research Institute for Reproductive Medicine and Genetics, Sichuan Jinxin Xi'nan Women's and Children's Hospital, Chengdu, China; Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China.
⁷ Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China.
⁸ First Affiliated Hospital of Shantou University, Shantou, China.
⁹ Motic China Group CO., LTD., Xiamen, China.
¹⁰ Jinxin Research Institute for Reproductive Medicine and Genetics, Sichuan Jinxin Xi'nan Women's and Children's Hospital, Chengdu, China; Provincial Key Laboratory of Molecular Pathology and Personalized Medicine, Center of Collaborative and Creative Center, Department of Pathology and Pathophysiology, Shantou University Medical College, Shantou, China. Electronic address: [email protected].

PMID: 39842636
DOI: 10.1016/j.jare.2025.01.025

Abstract

Introduction: Despite of numerous studies of the placenta, some molecular and cellular characteristics, particularly the relationship among different cell types, have not been well understood. We aim to investigate the basic and intricate details of cellular and molecular elements in early and late phase placentas to gain better understanding of the immune regulation of human reproductive process.

Methods: A novel combination of techniques of spatial transcriptomics(ST), multiple immunohistochemistry, and a dual labeling combining immunohistochemistry and (fluorescence in situ hybridization) FISH on normal and ectopic pregnancy and animal models was employed to investigate the placenta at tissue, cell, protein and molecular levels and to trace the fetal and maternal origin of every cell in early and late placentas.

Results: Original discoveries include early expression of immune checkpoint proteins in embryo trophoblasts even before implantation. The detailed distributional relationships among different cell types of fetal and maternal origins in placenta and decidua indicate an immune rejection of the mother towards the fetus and this was counterbalanced by immune inhibitory proteins and blocking antibody Immunoglobulin G4 (IgG4) at the junction between the fetus and the mother. In contrary to common believe, we found that vascular endothelial and glandular epithelial cells in the decidua remain maternal in origin and were not replaced by fetal cells. At term placenta, fetal immune cells infiltrated into the maternal side of the decidus and vice versa indicating a possible immune reaction between fetal and maternal immune systems and suggesting a possible immune mechanism for trigger of parturition. The ability of trophoblasts to create an immune suppressed environment was also supported by findings in ectopic pregnancy and the animal models.

Conclusion: The findings indicate a fetus-driven mechanism of immune balance involving both cellular and humoral immunity in human reproduction.

Keywords: Embryo; Fetus; Immunotolerance; Parturition; Placenta.