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Mechanics of human embryo compaction

Abstract

The shaping of human embryos begins with compaction, during which cells come into close contact1,2. Assisted reproductive technology studies indicate that human embryos fail compaction primarily because of defective adhesion3,4. On the basis of our current understanding of animal morphogenesis5,6, other morphogenetic engines, such as cell contractility, could be involved in shaping human embryos. However, the molecular, cellular and physical mechanisms driving human embryo morphogenesis remain uncharacterized. Using micropipette aspiration on human embryos donated to research, we have mapped cell surface tensions during compaction. This shows a fourfold increase of tension at the cell–medium interface whereas cell–cell contacts keep a steady tension. Therefore, increased tension at the cell–medium interface drives human embryo compaction, which is qualitatively similar to compaction in mouse embryos7. Further comparison between human and mouse shows qualitatively similar but quantitively different mechanical strategies, with human embryos being mechanically least efficient. Inhibition of cell contractility and cell–cell adhesion in human embryos shows that, whereas both cellular processes are required for compaction, only contractility controls the surface tensions responsible for compaction. Cell contractility and cell–cell adhesion exhibit distinct mechanical signatures when faulty. Analysing the mechanical signature of naturally failing embryos, we find evidence that non-compacting or partially compacting embryos containing excluded cells have defective contractility. Together, our study shows that an evolutionarily conserved increase in cell contractility is required to generate the forces driving the first morphogenetic movement shaping the human body.

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Fig. 1: Spatiotemporal map of tensions during human embryo compaction.
Fig. 2: Role of cell contractility and cell adhesion in regulating tensions during human embryo compaction.
Fig. 3: Mechanical signature of human embryos failing compaction.

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Data availability

Images and data are available from the BioImage Archive under accession number S-BIAD915. Simulations of compaction using surface tension values from experiments were used to illustrate different scenarios of surface tension changes. Source data are provided with this paper.

Code availability

Custom code is available at https://doi.org/10.5281/zenodo.10779533 (ref. 45).

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Acknowledgements

We thank the imaging platform of the Genetics and Developmental Biology unit at the Institut Curie (PICT-IBiSA@BDD), member of the French National Research Infrastructure France-BioImaging (ANR-10-INBS-04) for their outstanding support. We thank N. Kazdar, L. Delaroche and A. Le Dû and all the members of ART teams from the Clinique La Muette (Paris, France), the Clinique Pierre Chérest (Neuilly sur Seine, France) and the Hopital Cochin (Paris, France) for support with human embryo experiments. We thank all members of the Maître laboratory, Y. Bellaïche and M.-H. Verlhac for discussion and comments. We acknowledge the support with administrative issues from M.-H. Verlhac throughout this project. We are grateful to the patients who donated their surplus embryos to research. This project was funded by a Paris Sciences et Lettres (PSL) QLife (ANR-17-CONV-0005) grant to J.-L.M., C.P. and H.T. and the INSERM transversal programme Human Development Cell Atlas (HuDeCA) to J.-L.M. and C.P. Research in the laboratory of J.-L.M. is supported by the Institut Curie, the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé Et de la Recherche Médicale (INSERM) and is funded by grants from the Fondation Schlumberger pour l’Éducation et la Recherche through the Fondation pour la Recherche Médicale, the European Molecular Biology Organization Young Investigator program (EMBO YIP), Labex DEEP (ANR- 11-LABX-0044, part of the IDEX PSL ANR-10-IDEX-0001–02). J.F. is funded by a fellowship from the Fondation pour la Recherche Médicale (FDM202006011290). The work by H.T. and N.E. was supported by the CNRS and Collège de France. No fund from the European Research Council was used for this project.

Author information

Authors and Affiliations

Authors

Contributions

J.F., H.T., C.P. and J.-L.M. conceptualized the project and acquired funding. J.F. and J.-L.M. designed experiments. J.F. performed experiments. J.F., Ö.Ö. and J.-L.M. analysed the data. J.F., D.R.D., V.B.L and C.P. organized embryo collection. N.E. and H.T. wrote the theory and performed numerical simulations. J.-L.M. wrote the manuscript with inputs from J.F., N.E., H.T. and C.P.

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Correspondence to Jean-Léon Maître.

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Nature thanks Berenika Plusa, Hilde Van de Velde, Alpha Yap and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data figures and tables

Extended Data Fig. 1 Contact angle and surface tension measurements of individual embryos.

(a-c) Time course of external contact angles θe (a) and surface tensions γcm (b) and γcc/2 (c) of 5 representative embryos. Time starts from the first tension measurement. Each embryo is measured in 3–5 sessions, for which the mean ± SEM of 2 to 12 contacting cells are shown. (d-e) Mean ± SEM surface tension γcm (d) and γcc/2 (e) as a function of contact angles θe over successive measurement session of 5 representative embryos. Each embryo is measured in 3–5 sessions, for which the mean ± SEM of 2 to 12 contacting cells are shown. (f-g) Surface tension γcm (f) and γcc/2 (g) as a function of contact angles θe measured on 429 blastomeres from 14 embryos. Individual measurements are shown in grey (Pearson correlation values R = 0.624 for γcm (p < 10−47) and R = −0.135 for γcc (p > 10−2)) and mean ± SEM of 44 individual measurement sessions on 14 embryos are shown in red for γcm (Pearson correlation values of R = 0.740 (p < 10−8)) and in green for γcc R = 0.028 for γcc (p > 10−1)). p values obtained from the 2-tailed Pearson correlation critical values table.

Source Data

Extended Data Fig. 2 Cleavage stage of compacting and non-compacting blastomeres.

Blastomere stage, as determined by tracking successive cell divisions until the last tension measurement, of compacting, non-compacting and partially compacting embryos (7, 6 and 7 embryos and 40, 32 and 33 blastomeres respectively). For partially compacting embryos, the stages of compacted blastomeres, compacted blastomeres adjacent to excluded cells and excluded cells are indicated separately (13, 10 and 10 respectively).

Source Data

Extended Data Fig. 3 Volume and pressure changes during compaction.

(a-b) Hydrostatic pressure (a) and radius of curvature (b) of cells as a function of contact angles θe measured on 429 blastomeres from 14 embryos. Cleavage stages are determined based on tracking divisions on time lapse microscopy and are indicated with 4-, 8- and 16-cell stage blastomeres in grey, light and dark blue respectively. Black dots show blastomeres that cannot be staged with certainty. Pearson correlation R = 0.551 for the hydrostatic pressure and −0.044 for the radius of curvature. (c) Volume segmentation of embryos before and after compaction. Cells are shown in light blue when estimated to be the size of a 8-cell stage blastomere and larger, or shown in dark blue when the size of a 16-cell stage blastomere and smaller. (d) Volume of segmented cells as a function of the total number of cells in the embryo (118 cells from 21 embryos). Embryos with precisely 8 or 16 cells are indicated in light or dark blue respectively. Embryos with precisely 8 or 16 cells are used to statistically determine the characteristic size of 8- and 16-cell stage blastomeres respectively. Using these measurements, a size threshold is statistically determined at 49850 µm3 to classify cells as 8-cell stage blastomere and larger or 16-cell stage blastomere and smaller33. (e) Volume of 118 segmented cells as a function of the contact angle θe measured on 112 contacts from 21 embryos. Cells classified as 8-cell stage blastomere and larger are shown in light blue and cells classified as 16-cell stage blastomere and smaller are shown in dark blue. Pearson correlation between cell volume and contact angles are 0.176 for 8-cell stage blastomeres and larger (59 contacts, p > 10−1) and −0.034 for 16-cell stage blastomeres and smaller (53 contacts, p > 10−1). p values obtained from 2-tailed Pearson correlation tests.

Source Data

Extended Data Fig. 4 Recovery of compaction after ML7 and EDTA media treatments.

(a) Representative images of embryos in control medium (left) placed in medium containing 1:2000 ethanol (EtOH) for 45 min, then 10 µM ML7 for 45 min and after 3 h recovery in control medium (right). Scale bar, 20 µm. (b) Contact angles θe of embryos placed sequentially in control EtOH, ML7 and control media (Mean ± SEM of 59, 51, 44 contacts from 6 embryos). (c) Representative images of embryos placed in control medium (left) for 45 min, then EDTA containing medium for 30 min (center) and after 3 h recovery in control medium (right). Scale bar, 20 µm. (d) Contact angles θe of embryos placed sequentially in control, EDTA and control media (Mean ± SEM of 54, 43, 54 contacts from 6 embryos).

Source Data

Supplementary information

Supplementary Information

Supplementary table legends, video legends and references.

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Supplementary Note

Supplementary Tables

Supplementary Tables 1–8.

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Supplementary Video 1

Pre-implantation development of human embryos with full compaction. Time-lapse imaging of a human embryo from the four-cell stage to the blastocyst stage (shown in Fig 1b). Pictures taken every 30 min; scale bar, 40 µm.

Supplementary Video 2

Pre-implantation development of human embryos without compaction. Time-lapse imaging of a human embryo from the four-cell stage to the 16-cell stage (shown in Fig 3a). Pictures taken every 30 min; scale bar, 40 µm.

Supplementary Video 3

Pre-implantation development of human embryos with partial compaction. Time-lapse imaging of a human embryo from the four-cell stage to the blastocyst stage (shown in Fig 3e). Pictures taken every 30 min; scale bar, 40 µm.

Supplementary Video 4

Three-dimensional simulations of compaction. Simulations of compaction with distinct cell populations: blue blastomeres grow their tension γcm by a factor 3.2 and their tension γcc by 1.2 according to measurements shown in Fig. 3i,j; purple blastomeres do the same as blue ones (left), keep γcm steady and grow their tension γcc by 1.2 (middle) or keep γcm steady and grow their tension γcc by 2.4 (right). Tensions are linearly interpolated between the initial and final states in 15 steps.

Source data

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Firmin, J., Ecker, N., Rivet Danon, D. et al. Mechanics of human embryo compaction. Nature 629, 646–651 (2024). https://doi.org/10.1038/s41586-024-07351-x

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