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Publications of the Week

Single-Cell Assessment of Primary and Stem Cell-Derived Human Trophoblast Organoids As Placenta-Modeling Platforms

By February 28, 2024No Comments

This week we profile a recent publication in Developmental Cell by Matthew Shannon (pictured, right) and the lab of Dr. Alexander Beristain (left) at the BC Children’s Hospital Research Institute and UBC Faculty of Medicine.

Can you provide a brief overview of your lab’s current research focus?

A major focus of our lab investigates both the cellular and molecular processes that direct trophoblast cell biology in early placental development. Utilizing state-of-the-art cell isolating techniques and three-dimensional (3D) culture systems, we investigate trophoblast-intrinsic factors that regulate cell motility and early organ development, maternal-derived factors (predominantly immune cells) that play underlying roles in directing trophoblast fitness and function, and global gene expression and gene regulatory mechanisms specific to highly-specialized invasive subsets of trophoblasts.

What is the significance of the findings in this publication?

Historically, our ability to model early human trophoblast development has been technically and ethically limited. However, in 2018 two seminal discoveries changed this. First was the identification of conditions allowing long-term culture of primary human trophoblasts as 3D organoids. Second was the derivation of the first human trophoblast stem cell line. Together, these findings opened avenues for modelling human trophoblast development in vitro. While quickly adopted as a gold standard, these organoid models were never directly compared to trophoblasts found in vivo at single-cell resolution. This was the goal of our work.

Through this study, we highlight both similarities and differences between primary and stem cell-derived human trophoblast organoids, we provide evidence that current trophoblast stem cell lines do not resemble true trophoblast stem cells, and we indicate significant factors that need to be considered when selecting an optimal trophoblast model.

What are the next steps for this research?

Moving forward, we hope that trophoblast biologists (and anyone interested in studying trophoblast biology) will be able to use our findings to inform their model selection. To do this, we have published all of our raw data files and have synthesized the data reported in this study as an accessible resource, made available here. Excitingly, this resource allows for direct comparison of gene expression between trophoblasts found in vivo and in vitro at single-cell resolution.

Beyond this, our lab (along with other labs in our field) is now working to improve these human trophoblast models with the goal of better modelling the gene expression and differentiation patterns found in vivo.

Do you have any tips or advice you’d give other researchers working in this same system?

I think it is important to always start by reflecting on the strengths and limitations of your model. With regards to trophoblast organoids, my advice would be to consider what model best addresses the question you are trying to study. For example, primary organoids, like the placenta, are very heterogeneous, require larger sample sizes, and are not suitable for current gene editing approaches. On the other hand, stem cell organoids, being clonal in nature, bypass these limitations but suffer from altered progenitor cell biology and skewed differentiation.

Most importantly, as my colleague Gina says: always make sure that your reagents are fresh!

Do you have any plans to showcase this work at an upcoming conference?

I have been very lucky to share this work both locally and internationally. Most notably, I had the opportunity to share our findings at the 2023 Annual Meeting of the International Federation of Placenta Associations in Rotorua, New Zealand, where I received a Charlie L.W. Loke Award from Cambridge University for submitting a top-ranked abstract, as well as an Elsevier New Investigator Award for giving the best overall presentation at the meeting. Looking forward, the Beristain lab has many exciting talks scheduled for 2024 from individuals using these models.

This work was generously supported by funding from the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, and the British Columbia Children’s Hospital.