Cited by 54Gene Regulatory Network AnalysisCell Image Analysis TechniquesCellular Mechanics and Interactions

Inferring cell state by quantitative motility analysis reveals a dynamic state system and broken detailed balance

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Kimmel, Jacob C., Chang, Amy Y., Brack, Andrew S., Marshall, Wallace F.·2018·PLoS Computational Biology

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Abstract

Cell populations display heterogeneous and dynamic phenotypic states at multiple scales. Similar to molecular features commonly used to explore cell heterogeneity, cell behavior is a rich phenotypic space that may allow for identification of relevant cell states. Inference of cell state from cell behavior across a time course may enable the investigation of dynamics of transitions between heterogeneous cell states, a task difficult to perform with destructive molecular observations. Cell motility is one such easily observed cell behavior with known biomedical relevance. To investigate heterogenous cell states and their dynamics through the lens of cell behavior, we developed Heteromotility, a software tool to extract quantitative motility features from timelapse cell images. In mouse embryonic fibroblasts (MEFs), myoblasts, and muscle stem cells (MuSCs), Heteromotility analysis identifies multiple motility phenotypes within the population. In all three systems, the motility state identity of individual cells is dynamic. Quantification of state transitions reveals that MuSCs undergoing activation transition through progressive motility states toward the myoblast phenotype. Transition rates during MuSC activation suggest non-linear kinetics. By probability flux analysis, we find that this MuSC motility state system breaks detailed balance, while the MEF and myoblast systems do not. Balanced behavior state transitions can be captured by equilibrium formalisms, while unbalanced switching between states violates equilibrium conditions and would require an external driving force. Our data indicate that the system regulating cell behavior can be decomposed into a set of attractor states which depend on the identity of the cell, together with a set of transitions between states. These results support a conceptual view of cell populations as dynamical systems, responding to inputs from signaling pathways and generating outputs in the form of state transitions and observable motile behaviors.

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Crossref · 10.1371/journal.pcbi.1005927

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  • Quantitative measurements of cell motility behavior from time-lapse imaging data are sufficient to resolve states of MuSC activation and state transitions.

    “Previously, we demonstrated that quantitative measurements of cell motility behavior from time-lapse imaging data are sufficient to resolve states of MuSC activation and state transitions (Kimmel et al., 2018).”

    From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Kimmel et al., 2018

  • Visualization of cell behavior state space with t-SNE revealed heterogeneous cell behavior states, previously shown to reflect different states of MuSC activation.

    “The visualization of cell behavior state space with t-SNE (van der Maaten and Hinton, 2008) revealed heterogeneous cell behavior states, previously shown to reflect different states of MuSC activation (Fig. 1C) (Kimmel et al., 2018).”

    From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Kimmel et al., 2018

  • Concave transition rates are consistent with a model in which the peak transition rate represents a 'switch' between two states.

    “Concave transition rates are consistent with a model in which the peak transition rate represents a ‘switch’ between two states, corroborating our earlier observations made by cell behavior analysis (Kimmel et al., 2018).”

    From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Kimmel et al., 2018

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  1. [35]Cooper S, Sadok A, Bousgouni V, Bakal C. Apolar and polar transitions drive the conversion between amoeboid and mesenchymal shapes in melanoma cells. Molecular Biology of the Cell. 2015; 26(22): 4163– 4170. doi: 10.1091/mbc.E15-06-0382 26310441 PMC4710245 · DOI

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Authors
Kimmel, J. C., Chang, A. Y., Brack, A. S., & Marshall, W. F.
Affiliations
University of California, San Francisco (US)
Corresponding author
  • Kimmel, Jacob C.
  • Chang, Amy Y.
  • Brack, Andrew S.
  • Marshall, Wallace F.
Venue
PLoS Computational Biology
Published
2018-01-16
Volume
14
Issue
1
Pages
e1005927
ISSN
  • 1553-734X (ISSN-L)
  • 1553-7358
OpenAlex
W2950070192
Cited by
54
References
103
Citations by year
2026: 4 · 2025: 6 · 2024: 6 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 2
FWCI
2.13
Type
journal article
Language
en
Open access
Locations
  • PLoS Computational Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health (AR060868, AR061002)
  • National Science Foundation (MCB-1515456, 1650113, 1548297)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Cell Image Analysis Techniques
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
cell motility, cellular heterogeneity, state transitions, detailed balance, attractor states, muscle stem cells, myogenesis, mouse embryonic fibroblasts, nonequilibrium dynamics
MeSH terms
Algorithms, Animals, Cell Movement, Female, Fibroblasts, Kinetics, Leukocytes, Mononuclear, Male, Mice, Inbred C57BL, Muscles, Phenotype, Probability, Stem Cells, Signal Transduction, Cluster Analysis, Nonlinear Dynamics, Computational Biology, Mice

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