An Integrated Stochastic Model of Matrix-Stiffness-Dependent Filopodial Dynamics.
The ways that living cells regulate their behavior in response to their local mechanical environment underlie growth, development, and healing and are important to critical pathologies such as metastasis and fibrosis. Although extensive experimental evidence supports the hypothesis that this regulation is governed by the dependence of filopodial dynamics upon extracellular matrix stiffness, the pathways for this dependence are unclear. We therefore developed a model to relate filopodial focal adhesion dynamics to integrin-mediated Rho signaling kinetics. Results showed that focal adhesion maturation, i.e., focal adhesion links reinforcement and integrin clustering, dominates over filopodial dynamics. Downregulated focal adhesion maturation leads to the biphasic relationship between extracellular matrix stiffness and retrograde flow that has been observed in embryonic chick forebrain neurons, whereas upregulated maturation leads to the monotonically decreasing relationship that has been observed in mouse embryonic fibroblasts. When integrin-mediated Rho activation and stress-dependent focal adhesion maturation are combined, the model shows how filopodial dynamics endows cells with exquisite mechanosensing. Taken together, the results support the hypothesis that mechanical and structural factors combine with signaling kinetics to enable cells to probe their environments via filopodial dynamics.
The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China.
Bo
B
Cheng
The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China.
Min
M
Lin
The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China.
Yuhui
Y
Li
The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China.
Guoyou
G
Huang
School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.
Hui
H
Yang
The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China.
Guy M
GM
Genin
Department of Engineering, University of Cambridge, Cambridge, United Kingdom.
Vikram S
VS
Deshpande
The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China.
Tian Jian
TJ
Lu
The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China. Electronic address: fengxu@mail.xjtu.edu.cn.
Feng
F
Xu
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D022001:Focal Adhesions; D055595:Mechanical Phenomena; D051379:Mice; D008954:Models, Biological; D009068:Movement; D011554:Pseudopodia / Q000378:metabolism*; D013269:Stochastic Processes