Cells interacting over an extracellular matrix (ECM) exhibit
emergent behaviors, which are often observably different from
single-cell dynamics. Fibroblasts embedded in a 3-D ECM, for
example, compact the surrounding gel and generate an
anisotropic strain field, which cannot be observed in single cellinduced
gel compaction. This emergent matrix behavior results
from collective intracellular mechanical interaction and is crucial
to explain the large deformations and mechanical tensions that
occur during embryogenesis, tissue development and wound
healing. Prediction of multi-cellular interactions entails
nonlinear dynamic simulation, which is prohibitively complex to
compute using first principles especially as the number of cells
increase. Here, we introduce a new methodology for predicting
nonlinear behaviors of multiple cells interacting mechanically
through a 3D ECM. In the proposed method, we first apply Dual-
Faceted Linearization to nonlinear dynamic systems describing
cell/matrix behavior. Using this unique linearization method, the
original nonlinear state equations can be expressed with a pair of
linear dynamic equations by augmenting the independent state
variables with auxiliary variables which are nonlinearly
dependent on the original states. Furthermore, we can find a
reduced order latent space representation of the dynamic
equations by orthogonal projection onto the basis of a lower
dimensional linear manifold within the augmented variable
space. Once converted to latent variable equations, we superpose
multiple dynamic systems to predict their collective behaviors.
The method is computationally efficient and accurate as
demonstrated through its application for prediction of emergent
cell induced ECM compaction.
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A novel method for sensor-based quantification of single/multicellular force dynamics and stiffening in 3D matrices
Cells in vivo generate mechanical traction on the surrounding 3D extracellular matrix (ECM) and neighboring cells. Such traction and biochemical cues may remodel the matrix, e.g., increase stiffness, which, in turn, influences cell functions and forces. This dynamic reciprocity mediates development and tumorigenesis. Currently, there is no method available to directly quantify single-cell forces and matrix remodeling in 3D. Here, we introduce a method to fulfill this long-standing need. We developed a high-resolution microfabricated sensor that hosts a 3D cell-ECM tissue formed by self-assembly. This sensor measures cell forces and tissue stiffness and can apply mechanical stimulation to the tissue. We measured single and multicellular force dynamics of fibroblasts (3T3), human colon (FET) and lung (A549) cancer cells, and cancer-associated fibroblasts (CAF05) with 1-nN resolution. Single cells show notable force fluctuations in 3D. FET/CAF coculture system, mimicking cancer tumor microenvironment, increased tissue stiffness by three times within 24 hours.
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- Award ID(s):
- 1934991
- NSF-PAR ID:
- 10293186
- Date Published:
- Journal Name:
- Science Advances
- Volume:
- 7
- Issue:
- 15
- ISSN:
- 2375-2548
- Page Range / eLocation ID:
- eabf2629
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1126/sciadv.abf2629
