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Traction forces at the cytokinetic ring regulate cell division and polyploidy in the migrating zebrafish epicardium


Epithelial repair and regeneration are driven by collective cell migration and division. Both cellular functions involve tightly controlled mechanical events, but how physical forces regulate cell division in migrating epithelia is largely unknown. Here we show that cells dividing in the migrating zebrafish epicardium exert large cell–extracellular matrix (ECM) forces during cytokinesis. These forces point towards the division axis and are exerted through focal adhesions that connect the cytokinetic ring to the underlying ECM. When subjected to high loading rates, these cytokinetic focal adhesions prevent closure of the contractile ring, leading to multi-nucleation through cytokinetic failure. By combining a clutch model with experiments on substrates of different rigidity, ECM composition and ligand density, we show that failed cytokinesis is triggered by adhesion reinforcement downstream of increased myosin density. The mechanical interaction between the cytokinetic ring and the ECM thus provides a mechanism for the regulation of cell division and polyploidy that may have implications in regeneration and cancer.

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The data that support the findings of this study are available from the corresponding authors on reasonable request.

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The authors thank N. Castro and C. Garcia-Pastor for technical assistance, C. Norden, E. Martí and K. Poss for sharing mutant zebrafish and J. Muñoz’s custom FEM-platform EMBRYO, which has been utilized to implement the numerical model. M.U., A.G.-P. and I.T. were partially supported by pre-doctoral fellowships from the Spanish Ministry of Economy and Competitiveness ((MINECO)/FEDER BES-2013-062633, BES-2013-064698 and FPU-AP2010-5071, respectively). This work was supported by MINECO/FEDER (BFU2016-79916-P and BFU2014-52586-REDT to P.R.-C., BFU2015-65074-P to X.T., SAF2015-69706-R to A.R., BFU2016-75101-P and RYC-2014-15559 to V.C.), the Generalitat de Catalunya (2014-SGR-927 to X.T., 2014-SGR-1460 and PERIS SLT002/16/00234 to A.R. and the CERCA Programme), Instituto de Salud Carlos III-ISCIII/FEDER (Red de Terapia Celular—TerCel RD16/0011/0024 to A.R.), the European Research Council (CoG-616480 to X.T.), the European Commission (grant agreeement SEP-210342844 to P.R.-C. and X.T.), Obra Social ‘La Caixa’, and the prize ICREA Academia for excellence in research (P.R.-C.). IBEC is recipient of a Severo Ochoa Award of Excellence from MINECO.

Author information

M.U., A.R. and X.T. conceived the study and designed experiments. M.U., A.G.-P., I.T., J.F.A. and A.M.-L. performed experiments. M.U. and A.E.-A. analysed data. A.E.-A., V.C. and P.R.-C. carried out theoretical modelling. M.U., S.P. and L.A. carried out STORM imaging. All authors discussed the results. M.U. and X.T. wrote the manuscript with feedback from all authors. X.T. oversaw the project.


All experiments were performed in accordance with relevant guidelines and regulations, and conducted following procedures approved by the Ethics Committee on Experimental Animals of the PRBB (CEEA-PRBB).

Competing interests

The authors declare no competing interests.

Correspondence to Xavier Trepat.

Supplementary information

  1. Supplementary Information

    Supplementary Figs. 1–4, Supplementary Video Captions 1–10, Supplementary Table 1

  2. Reporting Summary

  3. Supplementary Video 1

    Collective cell migration of a monolayer of epicardial cells explanting from the heart

  4. Supplementary Video 2

    Myosin dynamics during cell migration (cells expressing Myosin-GFP)

  5. Supplementary Video 3

    Myosin dynamics with tractions overlaid after a follower cell spontaneously dies

  6. Supplementary Video 4

    Phase contrast images of a monolayer of epicardial cells with overlaid tractions

  7. Supplementary Video 5

    Tractions during a successful division overlaid on phase contrast images

  8. Supplementary Video 6

    Tractions during a successful division overlaid on myosin-GFP images

  9. Supplementary Video 7

    Paxillin-GFP during a successful cell division

  10. Supplementary Video 8

    Tractions during a failed division overlaid on myosin-GFP images

  11. Supplementary Video 9

    Paxillin images during a failed cell division

  12. Supplementary Video 10

    Calculation of average traction and myosin intensity

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Fig. 1: Zebrafish epicardium uses an unconventional mechanism of collective migration.
Fig. 2: Mechanics of epicardial migration.
Fig. 3: Epicardial cells exert traction forces during cytokinesis.
Fig. 4: A large number of cells are multinucleated due to cytokinetic failure.
Fig. 5: Reinforcement of CFAs leads to cytokinetic failure.