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Published Version (Advanced Access)CC BY-NC V4.0, Open Access
Journal article
Advantages, limitations, and innovative considerations for established and emerging models of human placental syncytiotrophoblast
Human Reproduction Update, Vol.Advanced access
27-Jan-2026
PMID: 41589863
Abstract
BACKGROUND
Understanding the mechanisms that promote or hinder healthy placental development and functionality is fundamental to advancing the field of fetal and reproductive medicine. Syncytiotrophoblast (STB) are highly specialized trophoblast which develop and gain functional maturity during the first trimester of pregnancy. STB are critical to many placental functions and are often implicated in the etiology of placental pathologies. Recent advancements in cell biology have facilitated the development of innovative in vitro STB model systems. However, as the variety of available in vitro STB models grows, a critical assessment of the strengths, limitations, and appropriate applications of both established and emerging model systems is important for the field.
OBJECTIVE AND RATIONALE
With this review, we set out to compile and synthesize current knowledge on in vitro modeling of STB. Using this information, we sought to develop a balanced and thoughtful discussion regarding the use and suitability of various in vitro STB models. Our approach is grounded in a framework that considers placental development and physiology, with a specific focus on the capability of different models to recapitulate and thus enable the study of human STB differentiation, development, function, and dysfunction.
SEARCH METHOD
This review assessed published literature sourced through the PubMed database. Search terms included ‘human placenta models,’ ‘syncytiotrophoblast models,’ ‘syncytiotrophoblast development,’ ‘trophoblast stem cells,’ ‘trophoblast organoids,’ and ‘trophoblast cell models.’ The literature search was limited to English-language publications available up to August 2025.
OUTCOMES
We provide a narrative which explores the features, potential applications, and limitations of various STB models, including explant systems, immortalized trophoblast cell lines, stem cell-derived trophoblast, and a range of established and emerging 3D culture systems. Our evaluation focuses on the potential of each model to address specific research questions and highlights the challenges associated with modeling different stages of STB development and different unique aspects of STB functionality. Moreover, while remarkable progress in developing STB models has been made, no single system fully recapitulates the complex in vivo features of STB formation and function. Rather than being exhaustive, this review seeks to provide an evidence-based perspective on STB modeling in vitro which can encourage the careful consideration of the strengths and limitations of STB models.
WIDER IMPLICATIONS
This review provides an overview of the in vitro STB models currently available and a commentary of the knowledge that these systems have contributed to our understanding of STB biology. While the field has made significant progress, ongoing refinement of existing models is essential for advancing our understanding of STB and their role in both the health and dysfunction of the human placenta. By summarizing the unique adaptations and physiological changes of STB throughout gestation and aligning these with the capabilities of current models, we have developed a framework to guide future research and innovation in STB modeling. This framework is underscored by the importance of selecting models which align with specific research questions and simultaneously acknowledging the inherent limitations in extrapolating data from any in vitro systems to the biological context of the developing human placenta. By generating this discussion, we hope to contribute to the ongoing refinement of placental research methodologies and to inspire continued innovation in STB model systems.
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Details
- Title
- Advantages, limitations, and innovative considerations for established and emerging models of human placental syncytiotrophoblast
- Authors
- Joshua J Fisher - Hunter Medical Research InstituteAshley Williams - University of the Sunshine Coast, Queensland, School of Health - BiomedicineFarhad Soheilmoghaddam - University of the Sunshine Coast, Queensland, School of Health - BiomedicineGeorgia R Kafer (Corresponding Author) - University of the Sunshine Coast, Queensland, School of Health - Biomedicine
- Publication details
- Human Reproduction Update, Vol.Advanced access
- Publisher
- Oxford University Press
- DOI
- 10.1093/humupd/dmaf034
- ISSN
- 1460-2369; 1355-4786
- PMID
- 41589863
- Copyright note
- © The Author(s) 2026. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
- Data Availability
- No new data were generated or analyzed in support of this research.
- Organisation Unit
- School of Health - Biomedicine; Australian Centre for Pacific Islands Research
- Language
- English
- Record Identifier
- 991201542102621
- Output Type
- Journal article
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