Identification of apelin/APJ signaling dysregulation in a human iPSC-derived granulosa cell model of Turner syndrome

  • Cell Death Discov. 2024 Nov 14;10(1):468. doi: 10.1038/s41420-024-02231-9.
Wei-Ju Chen  1 ,  Yi-Ya Chao  1 ,  Wei-Kai Huang  1 ,  Wei-Fang Chang  2  3 ,  Chii-Ruey Tzeng  2  3  4 ,  Chi-Hsuan Chuang  1 ,  Pei-Lun Lai  1 ,  Scott C Schuyler  5 ,  Long-Yuan Li  6 ,  Jean Lu  7  8  9  10
Affiliations
  • 1. Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan.
  • 2. Taipei Fertility Center, Taipei, 110, Taiwan.
  • 3. Taipei Medical Technology Co., Ltd, Taipei, 110, Taiwan.
  • 4. Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan.
  • 5. Department of Biomedical Sciences, College of Medicine, Chang Gung University, Division of Head and Neck Surgery, Department of Otolaryngology, Chang Gung Memorial Hospital, Taoyuan, 33302, Taiwan.
  • 6. Department of Life Sciences, National Chung Hsing University, Taichung, 402202, Taiwan. [email protected].
  • 7. Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan. [email protected].
  • 8. Department of Biomedical Sciences and Engineering, Tzu Chi University, Hualien, 97004, Taiwan. [email protected].
  • 9. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, 11490, Taiwan. [email protected].
  • 10. Genomics and System Biology Program, College of Life Science, National Taiwan University, Taipei, 10617, Taiwan. [email protected].
PMID: 39543104 DOI: 10.1038/s41420-024-02231-9
Abstract

The interaction between germ cells and somatic cells in the ovaries plays a crucial role in establishing the follicle reserve in mammals. Turner syndrome (TS) predominantly affects females who have a partial or complete loss of one X chromosome. Our understanding of the role that granulosa cells (GCs) play in TS disease progression and pathogenesis remains limited. In this study, we achieved GC differentiation efficiency of up to 80% from iPSCs. When attempting to replicate the differentiation process of embryonic granulosa cells, we observed the downregulation of specific genes-GATA4, FOXL2, AMHR2, CYP19A1, and FSH-in Turner syndrome-derived granulosa cells (TS-GCs). Additionally, we identified dysregulation of the cell cycle in TS-GCs. To uncover the endogenous defects in TS-GCs, we compared global transcriptome patterns between iPSC-derived granulosa cells from healthy individuals and those with Turner syndrome. The apelin/APJ pathway exhibited differential signaling between the healthy and TS groups. Supplementation with apelin ligands and activation of apelin/APJ downstream signaling via Akt/PKB restored cell cycle progression and marker gene expression. We hypothesize that during early embryonic development, failures in apelin/APJ signaling in GCs of Turner syndrome patients lead to abnormalities in ovarian development, ultimately resulting in early oocyte loss and infertility.

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