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Collective Chemotaxis through Noisy Multicellular Gradient Sensing.

ABSTRACT: Collective cell migration in response to a chemical cue occurs in many biological processes such as morphogenesis and cancer metastasis. Clusters of migratory cells in these systems are capable of responding to gradients of <1% difference in chemical concentration across a cell length. Multicellular systems are extremely sensitive to their environment, and although the limits to multicellular sensing are becoming known, how this information leads to coherent migration remains poorly understood. We develop a computational model of multicellular sensing and migration in which groups of cells collectively measure noisy chemical gradients. The output of the sensing process is coupled to the polarization of individual cells to model migratory behavior. Through the use of numerical simulations, we find that larger clusters of cells detect the gradient direction with higher precision and thus achieve stronger polarization bias, but larger clusters also induce more drag on collective motion. The trade-off between these two effects leads to an optimal cluster size for most efficient migration. We discuss how our model could be validated using simple, phenomenological experiments.

SUBMITTER: Varennes J

PROVIDER: S-EPMC4982970 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Collective Chemotaxis through Noisy Multicellular Gradient Sensing.

Varennes Julien J Han Bumsoo B Mugler Andrew A

Biophysical journal 20160801 3

Collective cell migration in response to a chemical cue occurs in many biological processes such as morphogenesis and cancer metastasis. Clusters of migratory cells in these systems are capable of responding to gradients of <1% difference in chemical concentration across a cell length. Multicellular systems are extremely sensitive to their environment, and although the limits to multicellular sensing are becoming known, how this information leads to coherent migration remains poorly understood. ...[more]

PMID: 27508447

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Project description:Mechanical stress patterns emerging from collective cell behavior have been shown to play critical roles in morphogenesis, tissue repair, and cancer metastasis. In our previous work, we constrained valvular interstitial cell (VIC) monolayers on circular protein islands to study emergent behavior in a controlled manner and demonstrated that the general patterns of cell alignment, size, and apoptosis correlate with predicted mechanical stress fields if radially increasing stiffness or contractility are used in the computational models. However, these radially symmetric models did not predict the existence of local regions of dense aligned cells observed in seemingly random locations of individual aggregates. The goal of this study is to determine how the heterogeneities in cell behavior emerge over time and diverge from the predicted collective cell behavior. Cell-cell interactions in circular multicellular aggregates of VICs were studied with time-lapse imaging ranging from hours to days, and migration, proliferation, and traction stresses were measured. Our results indicate that elongated cells create strong local alignment within preconfluent cell populations on the microcontact printed protein islands. These cells influence the alignment of additional cells to create dense, locally aligned bands of cells which disrupt the predicted global behavior. Cells are highly elongated at the endpoints of the bands yet have decreased spread area in the middle and reduced mobility. Although traction stresses at the endpoints of bands are enhanced, even to the point of detaching aggregates from the culture surface, the cells in dense bands exhibit reduced proliferation, less nuclear YAP, and increased apoptotic rates indicating a low stress environment. These findings suggest that strong local cell-cell interactions between primary fibroblastic cells can disrupt the global collective cellular behavior leading to substantial heterogeneity of cell behaviors in constrained monolayers. This local emergent behavior within aggregated fibroblasts may play an important role in development and disease of connective tissues. STATEMENT OF SIGNIFICANCE: Mechanical stress patterns emerging from collective cell behavior play critical roles in morphogenesis, tissue repair, and cancer metastasis. Much has been learned of these collective behaviors by utilizing microcontact printing to constrain cell monolayers (aggregates) into specific shapes. Here we utilize these tools along with long-term video microscopy tracking of individual aggregates to determine how heterogeneous collective behaviors unique to primary fibroblastic cells emerge over time and diverge from computed stress fields. We find that dense multicellular bands form from local collective behavior and disrupt the global collective behavior resulting in heterogeneous patterns of migration, traction stresses, proliferation, and apoptosis. This local emergent behavior within aggregated fibroblasts may play an important role in development and disease of connective tissues.

Dataset Information

Collective Chemotaxis through Noisy Multicellular Gradient Sensing.

Publications

Collective Chemotaxis through Noisy Multicellular Gradient Sensing.

Similar Datasets

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