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Matrix viscoplasticity and its shielding by active mechanics in microtissue models: experiments and mathematical modeling

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ABSTRACT

The biomechanical behavior of tissues under mechanical stimulation is critically important to physiological function. We report a combined experimental and modeling study of bioengineered 3D smooth muscle microtissues that reveals a previously unappreciated interaction between active cell mechanics and the viscoplastic properties of the extracellular matrix. The microtissues’ response to stretch/unstretch actuations, as probed by microcantilever force sensors, was dominated by cellular actomyosin dynamics. However, cell lysis revealed a viscoplastic response of the underlying model collagen/fibrin matrix. A model coupling Hill-type actomyosin dynamics with a plastic perfectly viscoplastic description of the matrix quantitatively accounts for the microtissue dynamics, including notably the cells’ shielding of the matrix plasticity. Stretch measurements of single cells confirmed the active cell dynamics, and were well described by a single-cell version of our model. These results reveal the need for new focus on matrix plasticity and its interactions with active cell mechanics in describing tissue dynamics.

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Stretch response of single smooth muscle cells.(a) Sideview schematic of cell adhered to micropost substrate (mPAD) in unstretched condition. The magnitude and direction of the deflections of the microposts are used to determine the forces exerted by the cell. (b) As the underlying mPAD substrate undergoes biaxial stretch, so too does the adherent cell. (c) Micrograph of SMC on an mPAD substrate with an effective micropost spring constant for small lateral deflections of 22 nN/μm. Red arrows show measured cellular forces, and white trace shows the outline of the cell. (d) Change in cellular forces upon application of 8% strain. (e) Strain profile applied to mPAD substrate results in the increases in cellular force shown by the circles in (f). (g) Force-strain curve showing viscoelastic response and recovery corresponding to that observed in the microtissues. The red curves in (f,g) are a fit using solely the cellular components of the model shown in Fig. 3.
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f4: Stretch response of single smooth muscle cells.(a) Sideview schematic of cell adhered to micropost substrate (mPAD) in unstretched condition. The magnitude and direction of the deflections of the microposts are used to determine the forces exerted by the cell. (b) As the underlying mPAD substrate undergoes biaxial stretch, so too does the adherent cell. (c) Micrograph of SMC on an mPAD substrate with an effective micropost spring constant for small lateral deflections of 22 nN/μm. Red arrows show measured cellular forces, and white trace shows the outline of the cell. (d) Change in cellular forces upon application of 8% strain. (e) Strain profile applied to mPAD substrate results in the increases in cellular force shown by the circles in (f). (g) Force-strain curve showing viscoelastic response and recovery corresponding to that observed in the microtissues. The red curves in (f,g) are a fit using solely the cellular components of the model shown in Fig. 3.

Mentions: To provide an independent assessment of the contribution of the cells to the microtissues’ mechanics, we measured the time-dependent mechanical response of single SMCs to an applied stretch. Micropost array detectors (mPADs)2324 constructed on flexible substrates reported the cells’ traction force dynamics as the mPADs were stretched biaxially with time courses analogous to that applied to the microtissues. This stretching is shown schematically in Fig. 4a,b and for a cell in Fig. 4c,d. As illustrated in Fig. 4e, the cells were subjected to a linearly increasing strain reaching a maximum of 10% over 3 minutes, followed by a linear decrease in strain back to the initial state over the same time interval, and then a 15 min strain-free observation period. Figure 4c,d show the increase in traction forces generated by a cell from the unstrained to the maximally strained state. Figure 4f shows the time evolution of the summed magnitudes of the individual forces exerted on the microposts, , which provides a measure of the overall contractile state of the cell, as the microposts are all bent towards the cell’s center by the cellular traction forces. As shown in Fig. 4g, the response of the total force to applied stretch is qualitatively similar to the stress-strain curves in the microtissue system: at the cessation of stretch, the total cellular force is lower than the initial value, and slowly recovers toward the initial value during the 15 minute observation period following the stretch protocol.


Matrix viscoplasticity and its shielding by active mechanics in microtissue models: experiments and mathematical modeling
Stretch response of single smooth muscle cells.(a) Sideview schematic of cell adhered to micropost substrate (mPAD) in unstretched condition. The magnitude and direction of the deflections of the microposts are used to determine the forces exerted by the cell. (b) As the underlying mPAD substrate undergoes biaxial stretch, so too does the adherent cell. (c) Micrograph of SMC on an mPAD substrate with an effective micropost spring constant for small lateral deflections of 22 nN/μm. Red arrows show measured cellular forces, and white trace shows the outline of the cell. (d) Change in cellular forces upon application of 8% strain. (e) Strain profile applied to mPAD substrate results in the increases in cellular force shown by the circles in (f). (g) Force-strain curve showing viscoelastic response and recovery corresponding to that observed in the microtissues. The red curves in (f,g) are a fit using solely the cellular components of the model shown in Fig. 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5037370&req=5

f4: Stretch response of single smooth muscle cells.(a) Sideview schematic of cell adhered to micropost substrate (mPAD) in unstretched condition. The magnitude and direction of the deflections of the microposts are used to determine the forces exerted by the cell. (b) As the underlying mPAD substrate undergoes biaxial stretch, so too does the adherent cell. (c) Micrograph of SMC on an mPAD substrate with an effective micropost spring constant for small lateral deflections of 22 nN/μm. Red arrows show measured cellular forces, and white trace shows the outline of the cell. (d) Change in cellular forces upon application of 8% strain. (e) Strain profile applied to mPAD substrate results in the increases in cellular force shown by the circles in (f). (g) Force-strain curve showing viscoelastic response and recovery corresponding to that observed in the microtissues. The red curves in (f,g) are a fit using solely the cellular components of the model shown in Fig. 3.
Mentions: To provide an independent assessment of the contribution of the cells to the microtissues’ mechanics, we measured the time-dependent mechanical response of single SMCs to an applied stretch. Micropost array detectors (mPADs)2324 constructed on flexible substrates reported the cells’ traction force dynamics as the mPADs were stretched biaxially with time courses analogous to that applied to the microtissues. This stretching is shown schematically in Fig. 4a,b and for a cell in Fig. 4c,d. As illustrated in Fig. 4e, the cells were subjected to a linearly increasing strain reaching a maximum of 10% over 3 minutes, followed by a linear decrease in strain back to the initial state over the same time interval, and then a 15 min strain-free observation period. Figure 4c,d show the increase in traction forces generated by a cell from the unstrained to the maximally strained state. Figure 4f shows the time evolution of the summed magnitudes of the individual forces exerted on the microposts, , which provides a measure of the overall contractile state of the cell, as the microposts are all bent towards the cell’s center by the cellular traction forces. As shown in Fig. 4g, the response of the total force to applied stretch is qualitatively similar to the stress-strain curves in the microtissue system: at the cessation of stretch, the total cellular force is lower than the initial value, and slowly recovers toward the initial value during the 15 minute observation period following the stretch protocol.

View Article: PubMed Central - PubMed

ABSTRACT

The biomechanical behavior of tissues under mechanical stimulation is critically important to physiological function. We report a combined experimental and modeling study of bioengineered 3D smooth muscle microtissues that reveals a previously unappreciated interaction between active cell mechanics and the viscoplastic properties of the extracellular matrix. The microtissues’ response to stretch/unstretch actuations, as probed by microcantilever force sensors, was dominated by cellular actomyosin dynamics. However, cell lysis revealed a viscoplastic response of the underlying model collagen/fibrin matrix. A model coupling Hill-type actomyosin dynamics with a plastic perfectly viscoplastic description of the matrix quantitatively accounts for the microtissue dynamics, including notably the cells’ shielding of the matrix plasticity. Stretch measurements of single cells confirmed the active cell dynamics, and were well described by a single-cell version of our model. These results reveal the need for new focus on matrix plasticity and its interactions with active cell mechanics in describing tissue dynamics.

No MeSH data available.


Related in: MedlinePlus