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Biomechanics

The fibrous character of pericellular matrix mediates cell mechanotransduction

(D-136) The fibrous character of pericellular matrix mediates cell mechanotransduction

Friday, October 13, 2023

9:30 AM – 10:30 AM PDT

Location: Exhibit Hall - Row D - Poster # 136

Primary Investigator(s)

XP

Xiangjun Peng

Fellow
Washington University in St. Louis, United States

Co-Author(s)

YH

Yuxuan Huang

Fellow
Washington University in St. Louis, United States

Presenting Author(s)

GG

Guy Genin, PhD

Harold and Kathleen Faught Professor
Washington University in St Louis
Saint Louis, Missouri, United States

Introduction::

Cells in solid tissues sense and respond to mechanical signals that are transmitted through extracellular matrix (ECM) over distances that are many times their size. This long-range force transmission is known to arise from strain-stiffening and buckling in the collagen fiber ECM network, but must also pass through the denser pericellular matrix (PCM) that cells form by secreting and compacting nearby collagen. However, the role of the PCM in the transmission of mechanical signals is still unclear. We therefore studied an idealized computational model of cells embedded within fibrous collagen ECM and PCM. Our results suggest that the smaller network pore sizes associated with PCM attenuates tension-driven collagen-fiber alignment, undermining long-range force transmission and shielding cells from mechanical stress. However, elongation of the cell body or anisotropic cell contraction can compensate for these effects to enable long distance force transmission. Results are consistent with recent experiments that highlight an effect of PCM on shielding cells from high stresses. Results have implications for the transmission of mechanical signaling in development, wound healing, and fibrosis.

Materials and Methods:: We first studied how the fibrous nature of the ECM and PCM affect force sensing, compared to linear elastic or linear hyperelastic ECM and PCM. We then quantitatively investigated how PCM properties, cell shape and polarization modulate the transmission of cell contractile forces. Finally, we evaluated how PCM affects the stresses transduced by cells in a far field stretch. We tested the hypotheses that the PCM attenuates long-range force transmission, cell-cell communication, and stress transfer to cells, and that the fibrous nature of the PCM accentuates this.

To study the effects of the PCM on cell-level mechanotransduction, we modeled an axisymmetric, ellipsoidal, cell centered within an ellipsoidal region of PCM that in turn was centered within a cylinder of a less dense, “far field” ECM. Cell contractility was modeled by a uniform contractile strain, as is appropriate for the early stages of cell spreading within a collagen ECM. The fibrous mechanobiological environment in was approximated by a network-inspired constitutive model.
(Wang et al., 2014). We systematically evaluated the effects of PCM and the key material parameters on force transmission, cell mechanosensation, and strain shielding. For comparison, we also studied linear and nonlinear elastic ECM and PCM. Simulations were performed in the COMSOL environment (COMSOL, Inc., Burlington, MA). The nonlinear constitutive model was used, and finite deformation was modeled.

Results, Conclusions, and Discussions::

As a comparison case, we first considered a contractile cell with no PCM. As expected from earlier studies (Alisafaei et al., 2021; Hall et al., 2016; Wang et al., 2014), displacement fields around cells embedded within linear elastic (Fig. 1a) or neo-Hookean (Fig. 1b) ECM decayed rapidly compared to displacement fields in fibrous ECM (Fig. 1c). Adding a relatively stiff, linear elastic or neo-Hookean PCM layer had moderate effects on displacement fields in linear elastic (Fig. 1d) and neo-Hookean (Fig. 1e) ECM, but much greater and diametrically opposite effects in fibrous PCM and ECM (Fig. 1f).

These trends are evident in plots of the normalized displacement versus the normalized distance along the midplane of the cylinder. As expound upon by Wang et al. (Wang et al., 2014), in the absence of PCM, displacement decays in a linear elastic ECM following the scaling of the Eshelby solution (Fig. 1g). In a neo-Hookean ECM, the decay is more rapid still (Fig. 1h). On the contrary, the scaling in a fibrous ECM is much slower (Fig. 2i), less than , which indicates that force transmission is long-range.

Addition of PCM had opposite effects in fibrous and non-fibrous systems. In a linear elastic or neo-Hookean system, the decay of displacement was attenuated by the PCM (Fig. 1), but in a fibrous system decay was accelerated by the PCM (Fig. 1i). However, for the fibrous ECM, due to strain-stiffening, the relatively stiff PCM has the opposite effect. The smaller pore size of the PCM reduces the collagen network reorientation underlying strain-stiffening, and thus reduces the associated long-range force transmission. The decay in displacement thus accelerates towards that observed in linear elastic and neo-Hookean systems (Fig. 1i). However, the fibrous system does retain greater long-range force transmission capacity than the other two systems because even in the relatively dense, fibrous PCM, the collagen network can still realign and strain-stiffen in response to stretch.

Acknowledgements (Optional): :

This work was supported by the NSF through the NSF Science and Technology Center for Engineering Mechanobiology (grant CMMI 1548571) and grant OIA-2219142, and by the NIH through grants R01AR077793, R01HL159094, and R01DK131177.

References (Optional): :

Alisafaei, F., Chen, X., Leahy, T., Janmey, P.A., Shenoy, V.B., 2021. Long-range mechanical signaling in biological systems. Soft Matter 17, 241-253.

Alisafaei, F., Jokhun, D.S., Shivashankar, G.V., Shenoy, V.B., 2019. Regulation of nuclear architecture, mechanics, and nucleocytoplasmic shuttling of epigenetic factors by cell geometric constraints. Proceedings of the National Academy of Sciences 116, 13200-13209.

Wang, H., Abhilash, A.S., Chen, Christopher S., Wells, Rebecca G., Shenoy, Vivek B., 2014. Long-Range Force Transmission in Fibrous Matrices Enabled by Tension-Driven Alignment of Fibers. Biophysical Journal 107, 2592-2603.