The cerebellum has a unique morphology characterized by fine folds called folia. During cerebellar morphogenesis, folia formation (foliation) proceeds with granule cell (GC) proliferation in an external granular layer, and subsequent cell migration to an internal granular layer (IGL). GC migration is guided along Bergmann glial (BG) fibers, whose orientation depends on the deformation of cerebellar tissue during folia formation. The aim of this study is to investigate the contribution of the fiber-guided GC migration on folia formation from a mechanical viewpoint. Based on a continuum mechanics model of cerebellar tissue deformation and GC dynamics, we simulated foliation process caused by GC proliferation and migration. By changing migration speeds, we showed that the fiber-guided GC migration caused the non-uniform accumulation of GCs and folia lengthening. Furthermore, the simulation of impaired GC migration under pathological conditions, where GCs did not migrate along BG fibers, revealed that fiber-guided GC migration was necessary for folia lengthening. These simulation results successfully recapitulated the features of physiological and pathological foliation processes and validated the mechanisms that guidance of GC migration by BG fibers causes folia lengthening accompanied by non-uniform IGL. Our computational approach will help us understand biological and physical morphogenesis mechanisms, facilitated by interactions between cellular activities and tissue behaviors.

Keywords

Cerebellar morphogenesis, Foliation, Finite element analysis, Continuum mechanics, Cell migration, Tissue growth

Paper information

[Advance Publication] (Proper information for citation will be announced after formal publication)

An individual trabecula in a cancellous bone is a porous material consisting of a lamellar bone matrix and interstitial fluid in a lacuno-canalicular porosity. The flow of interstitial fluid created by the application of mechanical load to a bone is considered to stimulate osteocytes for regulating bone remodeling, as well as enhance the transport of signaling molecules. The purpose of this study is to investigate, based on poroelastic theory, the flow-induced stimuli given to the osteocytes embedded in an individual lamellar trabecula. A single trabecula was modeled as a two-dimensional poroelastic slab composed of multiple layers subjected to cyclic uniaxial and bending loading. To consider the spatial variations in material properties due to lamellar structure of the trabecula, each layer was assumed to have a different value of permeability. By analytically solving the diffusion equation obtained from poroelasticity, we developed a solution for the interstitial fluid pressure in the lacuno-canalicular porosity within the single trabecula. Based on the solution obtained, we demonstrated the distribution of seepage velocity across the trabecula and qualitatively assessed the mechanical stimuli given to the osteocytes. The results suggested that osteocytes close to the trabecular surfaces are normally exposed to larger flow stimuli than those located around the center of the trabecula, regardless of the loading conditions and the spatial variations in permeability. On the other hand, osteocytes around the center of the trabecula, particularly with relatively large inner permeability, are stimulated by the fluid flow when the bending load is more dominant than the uniaxial load. Our theoretical approach might provide a better understanding of the effect of the spatial variations in bone material properties on the flow-mediated cellular mechanotransduction and signal transport for bone remodeling.

Keywords

Interstitial fluid flow, Trabecula, Lamellar structure, Osteocyte, Bending load, Poroelasticity

Paper information

Yoshitaka KAMEO, Yoshihiro OOTAO, Masayuki ISHIHARA, “Theoretical investigation of the effect of bending loads on the interstitial fluid flow in a poroelastic lamellar trabecula”, Journal of Biomechanical Science and Engineering, Vol.11, No.2 (2016), p.15-00663. doi:10.1299/jbse.15-00663. Final Version Released on June 24, 2016, Advance Publication Released on June 06, 2016.