Abstract
The dysregulation of growth factors is associated with defective trophoblast invasion, which leads to uteroplacental malperfusion due to the inadequate remodeling of spiral arteries. Pregnancy disorders, including preeclampsia, particularly early-onset preeclampsia, are closely related to compromised placental function caused by aberrant trophoblast invasion. Activin A, a growth factor detectable in serum that belongs to the transforming growth factor-β (TGF-β) superfamily, has been implicated in the development of preeclampsia, as evidenced by its elevated serum levels and its role in regulating trophoblast invasion. However, the existing research on its regulatory mechanisms in trophoblast invasion has focused mainly on intracellular, nonsecretory epithelial-mesenchymal transition (EMT) markers in conventional trophoblast cell lines, which limits its translational relevance to clinical applications. In this study, we performed small RNA sequencing combined with cell biology studies in primary human trophoblast and 2D human trophoblast stem cell models and revealed that the upregulation of the SOX4 (SRY-box transcription factor 4) and miR-103a-3p induced by activin A contributes to trophoblast invasion and potential extravillous differentiation. The bioinformatic analysis of proteomic and microRNA profiles from public databases revealed increased expression of the activin A protein and exosomal miR-103a-3p in maternal blood during the second trimester of pregnancy complicated by preeclampsia. Overall, our integrated approach reveals the regulatory mechanism by which activin A, SOX4, and miR-103a-3p regulate human trophoblast invasion and EVT differentiation, highlighting their potential as early diagnostic biomarkers for preeclampsia.
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Data availability
The data are available upon reasonable request. The raw small RNA sequencing data reported in this paper have been deposited in the Genome Sequence Archive for Human (GSA-Human) under accession No. HRA008074 and are available upon reasonable request.
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Acknowledgements
The authors extend their sincere gratitude to the hard work of the staff at British Columbia’s Women’s Hospital’s CARE Program for recruiting participants for our study. Additionally, we would like to thank Dr. Jingsong Wang at the Imaging Core Team of British Columbia’s Children’s Hospital Research Institute for helping with the microscopy imaging.
Funding
This work was supported by a Canadian Institutes of Health Research operating grant (PJT-183796 to PCKL and AGB), a Canadian Institutes of Health Research and a British Columbia Children’s Hospital graduate studentship (to MJS), and a graduate studentship of the Chinese Scholarship Council (to JMX).
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Conceptualization: JMX, MYD, and PCKL; Methodology: JMX, MYD, HZ, MJS, AGB, and PCKL; Formal analysis: JMX, MJS, and MYD; Investigation: JMX and HZ; Resources: PCKL and MYD; Writing—original draft: JMX; Writing—review and editing: HZ, MJS, AGB, MYD, and PCKL; Supervision: PCKL; Project administration: PCKL; Funding acquisition: PCKL and AGB.
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Xie, J., Shannon, M.J., Zhu, H. et al. Elucidating the roles of microRNA-103a-3p in trophoblast invasion and SOX4-mediated extravillous differentiation induced by activin A. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08665-6
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DOI: https://doi.org/10.1038/s41419-026-08665-6
