(B-42) Microstructure-Based Modeling of Primary Cilia Mechanics

Introduction:: A primary cilium, made of a microtubule axoneme enclosed in a cilium membrane, is a mechanosensing structure by sensing the membrane stress through components such as transmembrane proteins PC1/PC2 after the cilium is bent. The axoneme made of nine microtubule doublets is the main load-bearing structural component, while the transmembrane proteins on the cilium membrane are the main sensing components. But in all existing models, no distinction was made between these two components, and the stress calculated from the structural component (axoneme) was used to explain the sensing location, which can be totally misleading, since it is irrelevant to the stress in the sensing component (cilium membrane). For the first time, we developed a microstructure-based primary cilium model by considering these two components separately.

Materials and Methods:: Computationally, we applied nonlinear finite element method with explicit time integration to model the detailed microstructure of the primary cilium, including nine microtubule doublets and surrounding cilium membrane. The contact interactions between microtubules and cilium membrane were considered, and the highly anisotropic properties and large deformation of the microtubules were accurately captured. In addition, we also developed a version of the cilium model by taking into account the actual microtubule length distributions obtained from electron microscopy (EM) imaging.

Analytically, we modeled the microtubules as anisotropic cylindrical shells and carefully compared the results between finite element simulations and the theoretical predictions.

Results, Conclusions, and Discussions:: First, we found that the microtubule doublets are significantly twisted during the cilium bending. Second, besides being cilium-length-dependent, we found the mechanical properties of the cilium are also highly deformation-dependent. More important, we found that the cilium membrane near the base is not in pure tension or compression as previously thought, but in bending stress due to high curvature change. This will change the picture of cilium mechanosensing to that the transmembrane proteins are activated by membrane curvature change rather than membrane stretching. In addition, we re-derived the analytical solution of bending an orthotropic cylindrical shell for modeling microtubules and carefully compared the results between finite element simulations and the theoretical predictions. Excellent agreement was obtained, which is crucial for our microstructure-based modeling.

Acknowledgements (Optional): : Zhangli Peng acknowledges support from NSF-DMS (project grant 1951526). Andrew Resnick acknowledges support from NIH (project grant 1R15GM132829-01) and NSF-DMS (project grant 1951568). Y.-N. Young acknowledges support from NSF-DMS (project grant 1951600) and Flatironinstitute, part of Simons Foundation.

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