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Hierarchical deep reinforcement learning reveals a modular mechanism of cell movement

Abstract

Time-lapse images of cells and tissues contain rich information about dynamic cell behaviours, which reflect the underlying processes of proliferation, differentiation and morphogenesis. However, we lack computational tools for effective inference. Here we exploit deep reinforcement learning (DRL) to infer cell–cell interactions and collective cell behaviours in tissue morphogenesis from three-dimensional (3D) time-lapse images. We use hierarchical DRL (HDRL), known for multiscale learning and data efficiency, to examine cell migrations based on images with a ubiquitous nuclear label and simple rules formulated from empirical statistics of the images. When applied to Caenorhabditis elegans embryogenesis, HDRL reveals a multiphase, modular organization of cell movement. Imaging with additional cellular markers confirms the modular organization as a novel migration mechanism, which we term sequential rosettes. Furthermore, HDRL forms a transferable model that successfully differentiates sequential rosettes-based migration from others. Our study demonstrates a powerful approach to infer the underlying biology from time-lapse imaging without prior knowledge.

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Fig. 1: Concepts and design to model cell movement with HDRL.
Fig. 2: Modelling Cpaaa migration in C. elegans embryogenesis.
Fig. 3: Modular organization of Cpaaa movement in HDRL and 3D time-lapse imaging.
Fig. 4: Migration of Cpaaa upon genetic perturbations.
Fig. 5: Validation and characterization of the TMM.
Fig. 6: TMM classification and 3D time-lapse imaging of mu_int_R and CANL migration.

Data availability

The data that support the findings of this study have been deposited at https://drive.google.com/drive/folders/1K5DeN2oTw_KXWgtDxaRMlTrc5MS46avY?usp=sharing. A 50 wild-type C. elegans dataset, embryonic data for Cpaaa training and the TMM evaluation, as well the data for mu_int_R case, are included, named WT50_release, Cpaaa_release, cpaaa_1(2,3) and mu_int_R_CANL_1(2), respectively.

Code availability

Source code with data information and several pre-trained models are available at https://github.com/daliwang/hdrl4cellmigration (https://doi.org/10.5281/zenodo.543098).

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Acknowledgements

We thank A. Santella for discussions and technical help and H. Shroff and Q. Morris for critiquing the manuscript. This study was partly supported by an NIH grant (R01GM097576) to Z.B. and D.W. Research in Z.B.’s laboratory is also supported by an NIH centre grant to MSKCC (P30CA008748). This research used resources of the Compute and Data Environment for Science (CADES) at the Oak Ridge National Laboratory, which is supported by the Office of Science of the US Department of Energy under contract no. DE-AC05-00OR22725.

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Authors and Affiliations

Authors

Contributions

Z.W., Y.X., D.W. and Z.B. designed the experiments. Z.W., J.Y. and Y.X. performed the experiments and analysed the data. Z.W., Y.X., D.W., J.Y. and Z.B. wrote the manuscript. D.W. and Z.B. supervised the project.

Corresponding authors

Correspondence to Dali Wang or Zhirong Bao.

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The authors declare no competing interests.

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Nature Machine Intelligence thanks Nico Scherf and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–5, Table 1 and Videos 1–4.

Reporting Summary

Supplementary Video 1

The migration of Cpaaa.

Supplementary Video 2

The Cpaaa training process.

Supplementary Video 3

The migration of mu_int_R.

Supplementary Video 4

The migration of CANL.

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Wang, Z., Xu, Y., Wang, D. et al. Hierarchical deep reinforcement learning reveals a modular mechanism of cell movement. Nat Mach Intell 4, 73–83 (2022). https://doi.org/10.1038/s42256-021-00431-x

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