From Snapshots to Development: Identifying the Gaps in the Development of Stem Cell‐based Embryo Models along the Embryonic Timeline

Abstract

In recent years, stem cell-based models that reconstruct mouse and human embryogenesis have gained significant traction due to their near-physiological similarity to natural embryos. Embryo models can be generated in large numbers, provide accessibility to a variety of experimental tools such as genetic and chemical manipulation, and confer compatibility with automated readouts, which permits exciting experimental avenues for exploring the genetic and molecular principles of self-organization, development, and disease. However, the current embryo models recapitulate only snapshots within the continuum of embryonic development, allowing the progression of the embryonic tissues along a specific direction. Hence, to fully exploit the potential of stem cell-based embryo models, multiple important gaps in the developmental landscape need to be covered. These include recapitulating the lesser-explored interactions between embryonic and extraembryonic tissues such as the yolk sac, placenta, and the umbilical cord; spatial and temporal organization of tissues; and the anterior patterning of embryonic development. Here, it is detailed how combinations of stem cells and versatile bioengineering technologies can help in addressing these gaps and thereby extend the implications of embryo models in the fields of cell biology, development, and regenerative medicine.

From Mice to Men: Generation of Human Blastocyst-Like Structures In Vitro

“…Moreover, Li et al observed that these structures recapitulated post-implantation polarization events on the molecular level ( Li et al, 2019 ). Importantly, however, current 2D in vitro culture methods for post-implantation morphogenesis of blastocysts and blastoids do not readily permit the formation of mural trophectoderm, associated parietal endoderm and the ectoplacental cone [current gaps in embryo model development are reviewed in Shankar et al (2021) ].…”

“…There can be little doubt that blastoids are a valuable addition to the collection of stem cell-based models. Compared to other stem cell-based embryo-like structures, including gastruloids, 2D micropatterned stem cells, post-implantation amniotic sac embryoids and embryonic-extraembryonic fusion embryoids [reviewed in Fu et al (2021) , Shankar et al (2021) ], blastoids have the unique potential to recapitulate the pre-implantation embryo and are therefore the singular model for studying this early stage of development in vitro.…”

Automated, High‐Throughput Phenotypic Screening and Analysis Platform to Study Pre‐ and Post‐Implantation Morphogenesis in Stem Cell‐Derived Embryo‐Like Structures

“…Typically, embryo models, including blastoids, [ 2 ] extraembryonic/embryonic peri‐implantation models, [ 3 ] and gastruloids, [ 4 ] are formed by coaxing stem cells within a non‐adhesive (micro‐) environment that supports their unrestricted self‐organization potential. [ 2c,5 ] Embryo models are capable of recapitulating sequences of developmental processes, [ 6 ] modeling developmental defects, [ 6c,7 ] and providing insights into the molecular regulators driving development. [ 2a,e,8 ] Moreover, they have the potential to reveal hidden complexities in embryo morphogenesis and the assemblage of cell lineages at various stages of development.…”

“…Technological advances in micro‐engineering platforms and image‐based analysis software have enabled researchers to realize some potential applications of clinical and pharmaceutical research using embryo models. [ 5d,17 ] 3D high‐content phenotypic screening requires a versatile platform to allow long‐term culture, imaging, and quantification; robust culture conditions to allow reproducibility; simple and efficient read‐out, and supervised analysis to extract the most reliable information. [ 18 ] Soluble factors or compounds’ screening can serve as a powerful tool to study the function of signaling pathways in development.…”