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  3. Single-cell transcriptome analyses reveal disturbed decidual microenvironment in women of advanced maternal age

Single-cell transcriptome analyses reveal disturbed decidual microenvironment in women of advanced maternal age

  • Clin Transl Med. 2025 Dec;15(12):e70541. doi: 10.1002/ctm2.70541.
Hongliang Xie 1 2,  Yu Lu 1 2,  Aolin Zhang 1 2,  Anqi Zheng 1 2,  Baofeng Rao 1 2,  Cuiyu Yang 3 4 5,  Anyao Li 1 2,  Wenbo Guo 1 2,  Linhua Hu 6,  Xiaoling Huang 6,  Chi Chiu Wang 7 8,  Songying Zhang 3 4 5,  Xiaohui Fan 1 2 8 9 10,  Lu Li 1 2 7 8 9
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences & Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 State Key Laboratory of Chinese Medicine Modernization, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 3 Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease, Hangzhou, China.
  • 5 Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Hangzhou, China.
  • 6 Department of Nursing, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Department of Obstetrics and Gynaecology, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, and Sichuan University-Chinese University of Hong Kong Joint Reproductive Medicine Laboratory, The Chinese University of Hong Kong, Hong Kong, China.
  • 8 International Science and Technology Cooperation Base of Chinese Medicine Modernization and Big Health, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, China.
  • 9 Modern Chinese Medicine and Reproductive Health Joint Innovation Center, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, China.
  • 10 The Joint-Laboratory of Clinical Multi-Omics Research between Zhejiang University and Ningbo Municipal Hospital of TCM, Ningbo Municipal Hospital of TCM, Ningbo, China.
PMID: 41407538 DOI: 10.1002/ctm2.70541
Abstract

Background: Advanced maternal age (AMA) increases pregnancy risk. However, uterine-specific mechanisms independent of oocyte and embryo quality remain poorly defined. This study aimed to characterise the decidual microenvironment in women with AMA to identify key pathological changes and regulatory pathways.

Methods and results: Through integrated histology, Organoid modelling, and high-resolution scRNA-seq of first-trimester decidua from women of AMA and controlled reproductive age, we uncovered a pathologically remodelled decidual microenvironment characterised by aberrant cellular states and pathological differentiation pathways, leading to a pro-fibrotic state and accompanied by immune cell dysfunction, and disrupted intercellular communication in the AMA decidua. Central to this pathology was hyperactivated TGF-β signalling, driving fibroblast-to-myofibroblast transition and extracellular matrix overproduction, thereby fuelling fibrosis. Aberrant TGF-β further impaired decidual stromal cell (DSC) differentiation, leading to the failure of the essential mesenchymal-to-epithelial transition. We identified PRR15 as a novel DSC-specific regulator that is markedly suppressed in AMA. PRR15 deficiency unleashed hyperactive TGF-β/SMAD signalling, directly causing decidualisation failure, enhanced fibrosis, and aborted DSC differentiation. Epithelial-mesenchymal transition and immune cell reprogramming towards pro-fibrotic transcriptional signatures further amplify the fibrotic pathology.

Conclusion: This study established the aged decidual microenvironment, orchestrated by dysregulated TGF-β signalling and PRR15 loss, as a critical independent determinant of reproductive failure in AMA. Thus, it unveils novel diagnostic and therapeutic targets and strategies.

Key points: We provide the first single-cell atlas of the human decidua in advanced maternal age (AMA). A novel PRR15-TGF-β axis is identified, where PRR15 loss drives stromal fibrosis and decidualisation failure. This study reveals that AMA-associated uterine fibrosis begins in the first trimester, shifting focus to maternal factors.

Keywords

advanced maternal age, decidualisation; decidua fibrosis, epithelial–mesenchymal transition, fibroblast–myofibroblast transition, PRR15‐TGF‐β axis, single cell RNA sequencing.

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