The people behind the papers – Taishi Fujimura and Isao Tamura Free

Isao Tamura (left) and Taishi Fujimura (right)

Isao, what questions is your lab trying to answer?

Our lab aims to understand the mechanisms of human embryo implantation, a process that remains largely unknown due to ethical and technical limitations.

Taishi, how did you come to work in the lab and what drives your research today?

When I was in high school, I was fascinated by the origin of life and its mysteries. This experience led me to pursue a career in obstetrics and gynaecology. As a doctor, I have witnessed many births and have seen new life come into the world, which raised new questions in my mind and made me want to learn more about where life begins. Fortunately, I joined a research lab working on endometrial organoids and I felt a strong connection to this field. I am now fully involved in endometrial research and eager to explore it further.

Isao and Taishi, tell us about the background of the field that inspired your work

In our laboratory, we have reported numerous findings on the role of stromal cell decidualization during implantation, as well as the establishment and maintenance of pregnancy, using primary human endometrial stromal cells derived from the human endometrium. This work has inspired our broader interest in the complex process of human embryo implantation, which involves intricate interactions between the embryo and the endometrium. However, it is not possible to directly observe the implantation process as it occurs in vivo. While significant progress has been made with current in vitro models, particularly endometrial organoids, these models fail to replicate the three-dimensional (3D) structure of the human endometrium, including both epithelial and stromal components, as well as the polarity of the epithelium. Furthermore, since these models are cultured within extracellular matrices such as Matrigel, they cannot accurately recreate the direct attachment between the embryo and the apical surface of the epithelial cells. Our goal is to construct an advanced 3D endometrial model that includes both epithelial and stromal cells, enabling the study of embryo implantation in a more physiological context.

Isao and Taishi, can you give us the key results of the paper in a paragraph?

We have developed an ‘improved’ endometrial organoid that includes endometrial epithelial cells exhibiting appropriate polarity, as well as endometrial stromal cells. By co-culturing this organoid with blastocysts in vitro, we successfully observed the four steps of implantation in mice (attachment, invagination, entosis and invasion) in real-time. Our results demonstrated that the implantation rate significantly increased upon administration of steroid hormones. Additionally, a portion of the blastocysts differentiated into trophoblast cells, while endometrial stromal cells differentiated into decidualized stromal cells. These findings were reported as an in vitro implantation model.

Taishi, when doing the research, did you have any particular result or eureka moment that has stuck with you?

When I discovered that endometrial stromal cells began to self-aggregate around themselves during monolayer co-culture with endometrial epithelial cells using medium optimized for organoids, it was a moment of both surprise and inspiration. This was because I realized that it was possible to construct a 3D structure without the need for Matrigel, and that the self-aggregation allowed the cells to organize themselves into a 3D structure while maintaining their inherent polarity.

Taishi, and what about the flipside: any moments of frustration or despair?

When observing the interaction between the 3D endometrial organoid and the blastocyst in real time, I found it very frustrating that a standard inverted microscope couldn't capture the dynamic processes accurately. Many confocal microscopes were also unusable due to dish compatibility issues. Moreover, since the organoids had substantial thickness, capturing the implantation process in three dimensions required acquiring many optical slices, which raised concerns about phototoxicity and made imaging conditions extremely difficult to optimize.

Isao and Taishi, why did you choose to submit this paper to Development?

We chose to submit our paper to Development because it is a leading journal in the field of developmental biology with a long-standing reputation for publishing pioneering work. Notably, Development was the first journal to publish the ground-breaking study on mouse endometrial organoids (Boretto et al., 2017), which laid the foundation for our current research. Given the journal's central role in disseminating key advances in organoid and implantation biology, we felt it was the most appropriate venue to present our work on the development of an improved endometrial organoid model and its application to in vitro implantation studies.

Taishi, what is next for you after this paper?

Following this paper, my next goal is to generate the improved endometrial organoid using human cells. By applying the principles established in our current model, I hope to build a physiologically relevant in vitro system that will allow us to better understand human implantation and its associated disorders.

Isao, where will this story take your lab next?

This story will guide our lab towards uncovering the mechanisms of human implantation and developing new therapeutic strategies for implantation failure. By refining our in vitro models, we aim to provide deeper insights into this critical, yet poorly understood, stage of early pregnancy.

Finally, let's move outside the lab – what do you like to do in your spare time?

IT: Outside the lab, I enjoy staying physically active. I do full-body exercises, like bodyweight training, and I occasionally practice judo as well. It helps me refresh both my body and mind. And most importantly – perhaps it goes without saying – I value spending time with my family.