Membrane related dynamics and the formation of actin in cells growing on micro-topographies: a spatial computational model

Abstract

BackgroundIntra-cellular processes of cells at the interface to an implant surface are influenced significantly by their extra-cellular surrounding. Specifically, when growing osteoblasts on titanium surfaces with regular micro-ranged geometry, filaments are shorter, less aligned and they concentrate at the top of the geometric structures. Changes to the cytoskeleton network, i. e., its localization, alignment, orientation, and lengths of the filaments, as well as the overall concentration and distribution of key-actors are induced. For example, integrin is distributed homogeneously, whereas integrin in activated state and vinculin, both components of focal adhesions, have been found clustered on the micro-ranged geometries. Also, the concentration of Rho, an intracellular signaling protein related to focal adhesion regulation, was significantly lower.ResultsTo explore whether regulations associated with the focal adhesion complex can be responsible for the changed actin filament patterns, a spatial computational model has been developed using ML-Space, a rule-based model description language, and its associated Brownian-motion-based simulator. The focus has been on the deactivation of cofilin in the vicinity of the focal adhesion complex. The results underline the importance of sensing mechanisms to support a clustering of actin filament nucleations on the micro-ranged geometries, and of intracellular diffusion processes, which lead to spatially heterogeneous distributions of active (dephosphorylated) cofilin, which in turn influences the organization of the actin network. We find, for example, that the spatial heterogeneity of key molecular actors can explain the difference in filament lengths in cells on different micro-geometries partly, but to explain the full extent, further model assumptions need to be added and experimentally validated. In particular, our findings and hypothesis referring to the role, distribution, and amount of active cofilin have still to be verified in wet-lab experiments.ConclusionLetting cells grow on surface structures is a possibility to shed new light on the intricate mechanisms that relate membrane and actin related dynamics in the cell. Our results demonstrate the need for declarative expressive spatial modeling approaches that allow probing different hypotheses, and the central role of the focal adhesion complex not only for nucleating actin filaments, but also for regulating possible severing agents locally.

Hydroxyl Groups Induce Bioactivity in Silica/Chitosan Aerogels Designed for Bone Tissue Engineering. In Vitro Model for the Assessment of Osteoblasts Behavior

“…Osteoblasts lose a large part of their cell organelles but gain long, thin, and branched cell processes by which the cells remain in contact with neighboring osteocytes, capillaries, and osteoblasts lining the bone surface. Osteogenic cells have a highly developed cytoskeleton, and it is known that their differentiation is regulated in part through mechanical forces imposed by their surrounding environment [35][36][37].…”

“…In non-migrating cells, mature large FAs can be formed or even localized in the cell body during migration. They are predominantly composed of vinculin, paxilin, α actinin, and FAKs (Focal Adhesion Kinases) [35,36,43,44].…”

Effect of Washing Treatment on the Textural Properties and Bioactivity of Silica/Chitosan/TCP Xerogels for Bone Regeneration

“…Spatiotemporal regulation of tension sustained at FAs has been described as essential for the regulation of cell migration and settlement pointing to extracellular matrix remodeling and new bone formation. Force-mediated FA signaling together with actin bundles organization in stress fibers regulates cell proliferation and differentiation [ 78 , 79 , 80 , 81 , 82 , 83 ]. Actin cytoskeleton immunolabelling in HOB ® , after 48 h in culture in the presence of SCS8T10_U, revealed that the osteoblasts were big, some of them elongated, with filopodial and lamellipodial emissions.…”

Modeling for (physical) biologists: an introduction to the rule-based approach

“…Alternative methods for specifying models include languages/formats with syntactic differences that tend to offer similar functionality [58, 62, 99, 100]; domain-specific languages that offer higher-level abstractions that can ease the task of model specification [101]; and embedded languages, which allow a modeler to leverage the power of a general-purpose programming language [69]. There are also BNGL extensions and other languages that enable modeling capabilities beyond what is available within the BNGL framework [67, 68, 102–107]. We note that rules and rule-based models are readily visualized [76–78, 93, 96, 105, 108, 109] and software tools exist that enable a visual approach to model specification, such as RuleBuilder [75] and Simmune [63, 104, 105].…”