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Published May 23, 2024 | Published
Journal Article Open

The first two blastomeres contribute unequally to the human embryo

Abstract

Retrospective lineage reconstruction of humans predicts that dramatic clonal imbalances in the body can be traced to the 2-cell stage embryo. However, whether and how such clonal asymmetries arise in the embryo is unclear. Here, we performed prospective lineage tracing of human embryos using live imaging, non-invasive cell labeling, and computational predictions to determine the contribution of each 2-cell stage blastomere to the epiblast (body), hypoblast (yolk sac), and trophectoderm (placenta). We show that the majority of epiblast cells originate from only one blastomere of the 2-cell stage embryo. We observe that only one to three cells become internalized at the 8-to-16-cell stage transition. Moreover, these internalized cells are more frequently derived from the first cell to divide at the 2-cell stage. We propose that cell division dynamics and a cell internalization bottleneck in the early embryo establish asymmetry in the clonal composition of the future human body.

Copyright and License

Acknowledgement

We thank the patients who volunteered embryos for this work. We thank Maria Luisa Pardinas, Maria José De los Santos Molina, and IVIRMA Valencia for securing access to Embryoscope movies; Mingshu Liao and Changhuei Yang for help on image preparation; and David Glover, Adiyant Lamba, and Angela Andersen for invaluable advice. Some drawings were adapted from BioRender (BioRender.com). This work was supported by the Human Science Frontiers Program (LT0022/2022-L to S.J.), the NOMIS Foundation (12540449 to M.Z.-G.), the Wellcome Trust (207415/Z/17/Z to M.Z.-G.), the Open Philanthropy Project (to M.Z.-G.), the Shuri & Kay Curci Foundation (to M.Z.-G.), and the Weston Havens Foundation (to M.Z.-G.).

Contributions

Conceptualization: S.J., M.M., and M.Z.-G.; methodology: S.J., M.M., and R.V.; software: R.V. and D.I.; formal analysis: S.J., M.M., C.K., E.M.P., L.I.-S., and R.V.; investigation: S.J., M.M., L.I.-S., and D.-Y.C.; resources: R.M., P.R., R.J.P., and M.Z.-G.; writing: S.J., M.M., and M.Z.-G.; visualization: S.J. and M.M.; supervision: D.I. and M.Z.-G.; funding acquisition: S.J., N.A., D.I., and M.Z.-G.

Code Availability

Data S1. Source code for the mathematical model presented in Figure 6.

Conflict of Interest

N.A. is the founder and CEO of Progenesis Inc.

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Additional details

Created:
May 30, 2024
Modified:
May 30, 2024