A computation model of the multi-layer brain-tumor-blood barrier structure under mechanical load.

Abstract

Mechanical forces are abundant within the tumor microenvironment, including the solid stress generated from tumor growth and shear stress from the blood flow and the cerebellum spinal fluid. In brain tumors, the blood-tumor barrier (BTB), which consists of brain tumor-initiating cells (BTIC), pericytes, basement membrane, and endothelial cells, limits the access of most therapeutic agents to the tumor. Our previous work showed brain tumor-initiating cells are sensitive to mechanical signals, and knocking down the mechanical sensitive ion channel Piezo2 disrupts the BTB in medulloblastoma. Understanding how mechanical forces are transmitted to the BTB is important to decipher the mechanism by which BTB integrity is regulated. In this work, a multi-layer computation model, which is composed of BTICs, pericytes, basement membrane, and endothelial cells, was constructed based on transmission electron microscopy images of the BTB. The mechanical properties of each layer were set as isotropically elastic with Young's modulus of 0.5 kPa for BTIC, 0.5 kPa for pericyte, 20 kPa for basement membrane, and 3 kPa for endothelial cell. The force generated by pericytes was applied to pericyte's edge, mimicking the force generated at the edge during contraction of the pericyte. The force generated by the pericyte was assigned as 7 nN, calculated based on traction force microscopy measurement. To study the stress distribution under mechanical loading, a spherical indenter with a radius of 1.5 µm was added to the top of the BTB structure to apply a force of 10 pN. The results showed that the pericyte-generated stress is transmitted to all cellular and extracellular BTB components and the basement membrane converts pericyte contraction into compressive stress applied onto the endothelial cell. When subjected to mechanical stimulation, the basement membrane bears most mechanical stress within the BTB.