A recent Nature study evaluates post-implantation development in humans using embryo-like models based on genetically unmodified human naïve embryonic stem cells (ESCs).

Study: Complete human day 14 post-implantation embryo models from naïve ES cells. Image Credit: Marko Aliaksandr / Shutterstock.com

Background

After implantation of the human embryo, a series of events resembling morphogenesis of the extraembryonic tissues are essential for gastrulation, future development, in addition to the right organization of embryonic cells.

Since a high rate of embryo loss occurs during this phase, it’s imperative to know the events related to morphogenesis. Although this information is crucial for understanding fertility issues and developmental defects, studies on this topic are related to each technical and ethical challenges.

It is feasible to culture structures derived from human blastocysts; nonetheless, these models don’t accurately represent the in vivo events and organization. Subsequently, there’s a must develop stem cell-derived embryo models to check post-implantation stages.

An efficient human integrated post-implantation embryo model should have a continuous presence of equivalents of significant cells, resembling trophoblasts, primitive endoderm, extra-embryonic mesoderm (ExEM), and pluripotent epiblast-like cells. This model should have outstanding embryonic compartments with appropriate morphological and structural organization, in addition to possess an appropriate embryonic disc, bilaminar disc, hypoblast, polarized amnion unit, polarized yolk sac, trophoblast-like compartment, and chorionic cavity.

Mouse naïve ESCs have been used to recapitulate ex utero to check post-gastrulation stages. Stem cell-derived synthetic whole embryo models (SWEMs) were developed, which were renamed SEMs, to check the post-implantation phase of human embryos.

Previous studies have shown that mouse SEMs can dynamically progress beyond the gastrulation stage and reach early organogenesis stages of development. Subsequently, mouse naïve pluripotent cells may be used as a possible source of embryonic and extra-embryonic tissues to develop “organ-filled” embryo models.

In regards to the study

The provision of optimized protocols for two-dimensional (2D) in vitro human pluripotent stem cells (PSC) to distinguish into mature cells could provide a greater understanding of the transcriptional, mechanical, and signaling pathways related to early embryogenesis.

Considering the recent progress in mouse SEMs and advancements in naïve human pluripotent stem cells (PSC) conditions, the present study evaluated the potential of using these cells to develop complex peri/post-implantation embryo-like structures that may progress to pre/peri-gastrulation stages ex utero.

Study findings

Using the strategy described in a mouse model, the present study generated self-organizing human post-implantation SEMs from naive ESCs. In contrast to mouse SEM derivation protocols, the present study protocol didn’t require genetic modification or overexpression of exogenous lineage aspects for naïve ESCs to distinguish into key embryonic lineages essential for developmental stages.

The self-organization capability of naïve PSCs to generate embryonic and extra-embryonic compartments, including the ExEM, was described. Notably, newly created ex utero human SEMs resembled the three-dimensional (3D) architecture and crucial developmental markers of in utero of natural human embryos, particularly from 7-8dpf to 13-14dpf based on Carnegie stages 5a-6a. Carnegie stages are a standardized system utilized by embryologists to explain the maturity of embryos.

An appropriate spatial allocation of cell lineages was observed, wherein definite embryonic and extra-embryonic compartments were formed within the absence of fertilization or interaction with maternal tissues. Importantly, this was achieved without the usage of an external targeted signaling pathway to induce self-organization of the aggregated cells. Thus, on the structural level, the newly developed human SEM significantly resembles but is just not similar to natural in utero conditions.

The generated embryonic-body (EB) didn’t contain probably the most basic and defining markers of integrated embryo models. For instance, EB-like aggregates lacked key cell lineages of developing embryos including visceral, trophoblast lineage, and parietal primitive endoderm.

Moreover, EBs lacked an embryonic disc, bilaminar disc, yolk sac, hypoblast, and surrounding trophoblast-like compartment, that are essential structural features of developing embryos. EB-like aggregates were also limited of their ability to progress structurally to the following developmental stages following initial aggregate formation. Thus, these EB aggregates don’t qualify as models for embryos.

Conclusions

It is necessary to check early human post-implantation development to raised understand human embryogenesis, which can even provide vital insights into early pregnancy loss and development of birth defects. The present study aimed to develop an embryo model containing all vital embryonic structures, which can help future research on early embryogenesis.

The EB aggregates formed on this study didn’t meet all criteria; subsequently, it can’t be used as a model to check embryo development. Considering the well-defined embryonic structures developed on this study, it is feasible that by overcoming limitations related to EB aggregate formation, this model may very well be used to check early embryogenesis.