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Naïve ESC-derived Human Blastoids as In-vitro Models of Human Blastocysts

Review of " Blastocyst-like structures generated from human pluripotent stem cells" from Nature by Stuart P. Atkinson

While recent research has described the development of structures that mimic certain aspects of early human post-implantation development [1-6], we lack the ability to model the early embryogenic events of the human blastocyst. Encouraged by the generation of stem-cell-derived blastocyst-like structures in mice, researchers led by Gary C. Hon and Jun Wu (University of Texas Southwestern Medical Center, Dallas, TX, USA) now report on the development of human "blastoids" generated from naïve human embryonic stem cells (ESCs) and their applicability to the study of early human development, early pregnancy loss, and early developmental defects [7].

Yu et al. began with naïve human ESCs given their reported competence for differentiation into both embryonic (epiblast) and extra-embryonic (trophectoderm and hypoblast) lineages [8-10]. Using a sequential three-dimensional differentiation strategy in AggreWell plates, the authors induced naïve human ESCs to self-organize into blastocyst-like structures in vitro that contained inner cell mass- and trophectoderm-like compartments with a visible cavity, which the authors termed "human blastoids." Overall, these cellular structures exhibited broadly comparable dimensions and cellular composition to early human blastocysts.

Immunofluorescence analysis then demonstrated the presence of epiblast-, trophectoderm-, and hypoblast-like cells within human blastoids, with cells adopting a spatial organization comparable to that observed in human blastocysts. In addition, single-cell RNA sequencing-based profiling indicated both the reproducibility of human blastoid derivation and the similarity of blastoid-derived cells to their supposed counterparts from pre-implantation human blastocysts.

The authors continued the in vitro culture of their human blastoids to determine their ability to self-organize into structures similar to peri-implantation embryos; encouragingly, blastoids displayed similarities to in-vitro cultured human blastocysts in that they attached to the culture plate, adopted a flattened structure, and displayed clearly segregated lineages, although all at a low frequency.

Overall, the authors propose the generation of human blastoids from naïve human ESCs as an exciting means to generate human blastocyst-like structure as an accessible, scalable, and versatile means of studying normal and abnormal human development and studying conditions such as early pregnancy loss. While the authors note limitations related to suboptimal human naïve ESC culture and the derivation protocols, they believe that human blastoids will soon provide a valuable basic and translational research model.

For more on the immense potential of human blastoids derived from naïve ESCs, stay tuned to the Stem Cells Portal!

References

  1. Moris N, Anlas K, van den Brink SC, et al., An in vitro model of early anteroposterior organization during human development. Nature 2020;582:410-415.
  2. Martyn I, Kanno TY, Ruzo A, et al., Self-organization of a human organizer by combined Wnt and Nodal signalling. Nature 2018;558:132-135.
  3. Simunovic M, Metzger JJ, Etoc F, et al., A 3D model of a human epiblast reveals BMP4-driven symmetry breaking. Nature Cell Biology 2019;21:900-910.
  4. Shao Y, Taniguchi K, Townshend RF, et al., A pluripotent stem cell-based model for post-implantation human amniotic sac development. Nature Communications 2017;8:208.
  5. Zheng Y, Xue X, Shao Y, et al., Controlled modelling of human epiblast and amnion development using stem cells. Nature 2019;573:421-425.
  6. Xue X, Sun Y, Resto-Irizarry AM, et al., Mechanics-guided embryonic patterning of neuroectoderm tissue from human pluripotent stem cells. Nature Materials 2018;17:633-641.
  7. Yu L, Wei Y, Duan J, et al., Blastocyst-like structures generated from human pluripotent stem cells. Nature 2021;591:620-626.
  8. Dong C, Beltcheva M, Gontarz P, et al., Derivation of trophoblast stem cells from naïve human pluripotent stem cells. eLife 2020;9:e52504.
  9. Linneberg-Agerholm M, Wong YF, Romero Herrera JA, et al., Naïve human pluripotent stem cells respond to Wnt, Nodal and LIF signalling to produce expandable naïve extra-embryonic endoderm. Development 2019;146.
  10. Guo G, Stirparo GG, Strawbridge SE, et al., Human naive epiblast cells possess unrestricted lineage potential. Cell Stem Cell 2021;28:1040-1056.e6.