Geometric control of capillary architecture via cell-matrix mechanical interactions

Abstract

Capillary morphogenesis is a multistage, multicellular activity that plays a pivotal role in various developmental and pathological situations. In-depth understanding of the regulatory mechanism along with the capability of controlling the morphogenic process will have direct implications on tissue engineering and therapeutic angiogenesis. Extensive research has been devoted to elucidate the biochemical factors that regulate capillary morphogenesis. The roles of geometric confinement and cell-matrix mechanical interactions on the capillary architecture, nevertheless, remain largely unknown. Here, we show geometric control of endothelial network topology by creating physical confinements with microfabricated fences and wells. Decreasing the thickness of the matrix also results in comparable modulation of the network architecture, supporting the boundary effect is mediated mechanically. The regulatory role of cell-matrix mechanical interaction on the network topology is further supported by alternating the matrix stiffness by a cell-inert PEG-dextran hydrogel. Furthermore, reducing the cell traction force with a Rho-associated protein kinase inhibitor diminishes the boundary effect. Computational biomechanical analysis delineates the relationship between geometric confinement and cell-matrix mechanical interaction. Collectively, these results reveal a mechanoregulation scheme of endothelial cells to regulate the capillary network architecture via cell-matrix mechanical interactions.

Vascularization and Angiogenesis in Tissue Engineering: Beyond Creating Static Networks

“…Apart from locally changing the mechanical properties of a matrix, this phenomenon provides another opportunity to control vascular organization in engineered tissues. Using a Matrigel assay in PDMS microwells of different shapes including circles, squares, triangles, and stars, Sun et al show that the HUVEC network near the boundary of the shapes has significantly higher densities and shorter mean cord length compared with the center regions [71]. Finite element analysis points out that physical confinement can tune gel displacement due to cellular contraction, resulting in variations in cellular tension.…”

Development of fibrin gel-microgroove model for microvascularization by endothelial cells

“…Substrate topography and geometry were reported to help new blood vessel formation via cell-matrix mechanical interactions [4]. In a previous study, Sukmana and Vermette cultured ECs for several days with paralleled fibers, which was made from polyethylene terephthalate (PET) and sandwiched by two layers of fibrin gel, for stimulating microvascularization [5].…”

Advances in Techniques for Probing Mechanoregulation of Tissue Morphogenesis

“…90 Microwells with arbitrary shapes (e.g., star, square, and triangle) were shown to module capillary topology via cell-matrix mechanical interactions. 13 Endothelial cells can form denser networks on acute angle corners than those on reflex angle corners in a star-shaped ECM structure. The geometric control of tissue morphogenesis has significant implications in microfabrication-based tissue models and scaffold design for tissue engineering.…”

“…12 As an example, geometric confinement has been demonstrated to regulate capillary network topology via cell-matrix mechanical interactions. 13 Tissue deformation has been shown to modulate vascular endothelial growth factor gradients and endothelial cell proliferation in deformable tissue constructs, coupling biochemical and mechanical tissue regulation. 14 Cell traction force has been demonstrated to control capillary network formation in vitro and in vivo by applying a Rho inhibitor and modulating extracellular matrix (ECM) elasticity.…”