In development, lineage segregation is coordinated in time and space. An important example is the mammalian inner cell mass, in which the primitive endoderm (PrE, founder of the yolk sac) physically segregates from the epiblast (EPI, founder of the fetus). While the molecular requirements have been well studied, the physical mechanisms determining spatial segregation between EPI and PrE remain elusive. Here, we investigate the mechanical basis of EPI and PrE sorting. We find that rather than the differences in static cell surface mechanical parameters as in classical sorting models, it is the differences in surface fluctuations that robustly ensure physical lineage sorting. These differential surface fluctuations systematically correlate with differential cellular fluidity, which we propose together constitute a non-equilibrium sorting mechanism for EPI and PrE lineages. By combining experiments and modeling, we identify cell surface dynamics as a key factor orchestrating the correct spatial segregation of the founder embryonic lineages.
We are grateful to H. Niwa for Dox regulatable PB vector; G. Charras for EzrinT567D cDNA; K. Jones for tdTomato ESCs, R26-Confetti ESCs, and laboratory assistance; M. Kinoshita for pPB-CAG-H2B-BFP plasmid; P. Humphreys and D. Clements for imaging support; G. Chu, P. Attlesey, and staff for animal husbandry; S. Pallett for laboratory assistance; C. Mulas for critical feedback on the project; T. Boroviak for single-cell RNA-seq; the EMBL Genomics Core Facility for sequencing; and M. Merkel for developing and sharing the original version of the 3D Voronoi code. This work was financially supported by BBSRC ( BB/Moo4023/1 and BB/T007044/1 to K.J.C. and J.N., Alert16 grant BB/R000042 to E.K.P.), Leverhulme Trust ( RPG-2014-080 to K.J.C. and J.N.), European Research Council ( 772798 -CellFateTech to K.J.C., 311637 -MorphoCorDiv and 820188 -NanoMechShape to E.K.P., Starting Grant 851288 to E.H., and 772426 -MeChemGui to K.F.), the Isaac Newton Trust (to E.K.P.), Medical Research Council UK (MRC program award MC_UU_00012/5 to E.K.P.), the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 641639 ( ITN Biopol , H.D.B. and E.K.P.), the Alexander von Humboldt Foundation (Alexander von Humboldt Professorship to K.F.), EMBO ALTF 522-2021 (to P.S.), Centre for Trophoblast Research (Next Generation fellowship to S.A.), and JSPS Overseas Research Fellowships (to A.Y.). The Wellcome-MRC Cambridge Stem Cell Institute receives core funding from Wellcome Trust ( 203151/Z/16/Z ) and MRC ( MC_PC_17230 ). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Yanagida A, Corujo-Simon E, Revell CK, et al. Cell surface fluctuations regulate early embryonic lineage sorting. Cell. 2022;185(5):777-793.e20. doi:10.1016/j.cell.2022.01.022
Yanagida, A., Corujo-Simon, E., Revell, C. K., Sahu, P., Stirparo, G. G., Aspalter, I. M., … Chalut, K. J. (2022). Cell surface fluctuations regulate early embryonic lineage sorting. Cell. Cell Press. https://doi.org/10.1016/j.cell.2022.01.022
Yanagida, Ayaka, Elena Corujo-Simon, Christopher K. Revell, Preeti Sahu, Giuliano G. Stirparo, Irene M. Aspalter, Alex K. Winkel, et al. “Cell Surface Fluctuations Regulate Early Embryonic Lineage Sorting.” Cell. Cell Press, 2022. https://doi.org/10.1016/j.cell.2022.01.022.
A. Yanagida et al., “Cell surface fluctuations regulate early embryonic lineage sorting,” Cell, vol. 185, no. 5. Cell Press, p. 777–793.e20, 2022.
Yanagida A, Corujo-Simon E, Revell CK, Sahu P, Stirparo GG, Aspalter IM, Winkel AK, Peters R, De Belly H, Cassani DAD, Achouri S, Blumenfeld R, Franze K, Hannezo EB, Paluch EK, Nichols J, Chalut KJ. 2022. Cell surface fluctuations regulate early embryonic lineage sorting. Cell. 185(5), 777–793.e20.
Yanagida, Ayaka, et al. “Cell Surface Fluctuations Regulate Early Embryonic Lineage Sorting.” Cell, vol. 185, no. 5, Cell Press, 2022, p. 777–793.e20, doi:10.1016/j.cell.2022.01.022.
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