Published May 23, 2024
| Version in press
Journal Article
Open
The first two blastomeres contribute unequally to the human embryo
Creators
-
1.
California Institute of Technology
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
© 2024 The Author(s). Published by Elsevier. Creative Commons Attribution (CC BY 4.0)
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.
Files
PIIS0092867424004550.pdf
Additional details
Related works
- Featured in
- Caltech News: https://www.caltech.edu/about/news/fetal-cells-can-be-traced-back-to-the-first-day-of-embryonic-development (URL)
- Nature: 10.1038/s41562-024-01867-y (DOI)
Funding
- International Human Frontier Science Program Organization
- LT0022/2022-L
- Nomis Foundation
- 12540449
- Wellcome Trust
- 207415/Z/17/Z
- Open Philanthropy Project
- Shurl and Kay Curci Foundation
- Weston Havens Foundation