Fluorescent microscopy image of an embryo model representing four tissue layers of this developmental stage. Cyan-labeled cells are clustered at the top of an ovoid structure, underneath them are yellow-labeled cells and under them red-labeled cells, and surrounding all three layers are white labeled cells.
Embryo models could help scientists understand stem cell differentiation, the development of organs, and how defects arise. Scientists imaged this embryo model after eight days in culture. It consists of four tissue structures: epiblast (cyan), yolk sac (yellow), extra-embryonic mesoderm cells with early chorionic cavity (red), and trophoblast layer (white).
Jacob Hanna

During embryonic stem cell (ESC) development, pluripotent stem cells transition from a naïve state into a primed state before they take their first steps toward a lineage commitment. Jacob Hanna, a stem cell biologist at the Weizmann Institute of Science, wanted to know why this transition occurs. To answer this question, Hanna and his team set out to develop an ex utero embryo model. 

Hanna recognized that the project was ambitious and could not be rushed. So, his team first studied the conditions for growing a normal embryo from a mouse outside of the uterus.1 Then they identified the cell types and conditions needed to develop a murine embryo from mouse embryonic cells.2 Finally, they developed the first human embryo model created from naïve human ESC.3  “It took a lot of iterations and trials,” Hanna said. 

The team differentiated the human naïve ESC into four subpopulations and cultured them at specific ratios to promote the development of embryonic tissues. While monitoring the ESC-based embryo model’s growth for important structures, they captured an image eight days after culture that included the epiblast, yolk sac, extra-embryonic mesoderm, and trophoblast. The team used atlases to compare the structures of their model to normally developed embryos. 

While some researchers anticipate studying embryos beyond the 14-day limit, Hanna stressed the importance of having a high quality model over longer culture periods. “It’s not about counting days; it’s about getting an embryo that looks like what it should,” Hanna emphasized.

According to Hanna, these models will help answer how a primed state benefits cell differentiation, understand developmental errors that lead to nonviable pregnancies, and improve organ development for transplantation.  

  1. Aguilera-Castrejon A, et al. Ex utero embryogenesis from pre-gastrulation to late organogenesis. Nature. 2021;593:119-124
  2. Tarazi S, et al. Post-gastrulation synthetic embryos generated ex utero from mouse naïve ESC. Cell. 2022;185(18):3290-3306
  3. Oldak B, et al. Complete human day 14 post-implantation embryo models from naïve ES cells. Nature. 2023;622:562-573