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Mechanical feedback drives asynchronous cell divisions during embryogenesis

Abdul N. Malmi-Kakkada1,2,*,†, Sumit Sinha3,*,‡,§, and D. Thirumalai3,4,∥

  • *These authors contributed equally to this work.
  • †Contact author: amalmikakkada@towson.edu
  • ‡Present address: Applied Mathematics (SEAS, Harvard University) & Data Science (Dana Farber Cancer Institute).
  • §Contact author: ssinha@g.harvard.edu
  • ∥Contact author: dave.thirumalai@gmail.com
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Phys. Rev. Research 7, 043027 – Published 7 October, 2025

DOI: https://doi.org/10.1103/z4y9-5f9f

Abstract

The initial stage of zebrafish morphogenesis is characterized by a synchronous to asynchronous transition (SAT) in cell divisions. The cells divide in unison in the synchronous phase, unlike in the asynchronous phase. Despite the widespread observation of SAT in multiple organisms, there is no theoretical framework to predict the critical number of cell cycles n* that mark the beginning of asynchronous division. Here, by probabilistically modeling cell cycle progression under the assumption that the distribution of cell division times is broadened, we predict the value of n* and the time at which the SAT occurs. The theory, supplemented by agent-based simulations, supports the hypothesis that the SAT emerges as a consequence of biomechanical feedback on cell division. Our results are in excellent agreement with experiments while also explaining the cell cycle lengthening that arises as a result of biomechanical feedback. The emergence of the asynchronous phase is due to increasing fluctuations in the cell cycle times with each round of cell division. We also make several testable predictions that further shed light on the role of biomechanical feedback in growing multicellular systems, such as during tissue and tumor growth.

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Phys. Rev. Research 7, 043027– Published 7 October, 2025
  • Received 22 December 2023
  • Accepted 8 September 2025
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Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.

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