Stem cell-based human embryo models: current knowledge and open questions

Abstract

Recently, the research field revolving around the stem cell-based modeling of the human embryo gained particular momentum when the first integrated models were designed with the aim to recapitulate the development of the entire early human conceptus. The underlying driving force to reconstruct embryo-like structures is the prospect of a more comprehensive understanding of the fundamental processes controlling early human embryogenesis including their deregulation causing reproductive failures, and the endeavor to use these embryo models for drug testing and disease modeling. Although efforts will continue to create improved models with steadily increasing fidelity to human embryogenesis, the next phase focusing on the application of human embryo models as a platform to address particular scientific questions is currently being entered. In this review, we discuss the benefits, promises and limitations associated with the use of non-integrated and integrated stem cell-based human embryo models in translational research and biomedical applications.

Fig. 1

Early human embryogenesis. Canonical lineage specification in the early human embryo, and illustration of the pre-implantation and post-implantation human embryo depicting its essential components (for details see the text)

Fig. 2

The non-integrated stem cell-based human embryo models. Comparison of the generation process, the modeled spatial condition, the represented embryonic period, and the main biological and structural characteristics (determined by transcriptional signature studies, antibody-based detection of marker expression and/or morphological analyses. For details see the text) of the reported non-integrated models. + indicates certain indications for the presence of this feature;—indicates the absence of this feature; +/− indicates that a specific type of neuronal gastruloid exhibits this feature and the other type does not; ? indicates that the existence of this structure is suggested but not finally proven; ND, not determined. The stem cell-based human embryo models’ designations were adopted from the authors according to the initial descriptions: MP colony (micropatterned colony) [21], PASE (post-implantation amniotic sac embryoid) [22, 23], PTED embryoid (peri-gastrulation trilaminar embryonic disc embryoid) [24], Epiblast model [25], Gastruloid [26], Neuronal gastruloid [27, 28]

Fig. 3

The integrated stem cell-based human embryo models. Comparison of the generation process, the modeled spatial condition, the represented embryonic period, and the main biological and structural characteristics (determined by transcriptional signature studies, antibody-based detection of marker expression and/or morphological analyses. F or details see the text) of the reported integrated models. + indicates certain indications for the presence of this feature; − indicates the absence of this feature; +/− indicates that specific types of blastoids exhibit this feature and other types do not; ( +) indicates that only limited evidence for the structure has been described; ? indicates that the existence of this structure is suggested but not finally proven; ND, not determined. The stem cell-based human embryo models’ designations were adopted from the authors according to the initial descriptions: Blastoid [–53], Extra-embryoid [54], Embryoid [60], E-assembloid (embryo-like assembloid) [55], Peri-gastruloid [56], SEM (stem-cell-based embryo model) [61], Bilaminoid [58], eX-embryoid (extra-embryonic niche and yolk sac haematopoiesis embryoid) [59], Gastruloid [57]

Fig. 4

The putative scope of applications of the different stem cell-based human embryo models. Evaluation of the stem cell-based human embryo models with regard to their putative usability for specific investigations or applications. − indicates that this embryo model cannot be used; + , + + , and + + + indicates ascending degrees of usability; +/− indicates that only specific types of this embryo model can be used. The stem cell-based human embryo models’ designations were adopted from the authors according to the initial descriptions: MP colony (micropatterned colony) [21], PASE (post-implantation amniotic sac embryoid) [22, 23], PTED embryoid (peri-gastrulation trilaminar embryonic disc embryoid) [24], Epiblast model [25], Gastruloid [26], Neuronal gastruloid [27, 28], Blastoid [–53], Extra-embryoid [54], Embryoid [60], E-assembloid (embryo-like assembloid) [55], Peri-gastruloid [56], SEM (stem-cell-based embryo model) [61], Bilaminoid [58], eX-embryoid (extra-embryonic niche and yolk sac haematopoiesis embryoid) [59], Gastruloid [57]