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Fiber Crimp Confers Matrix Mechanical Nonlinearity, Regulates Endothelial Cell Mechanosensing, and Promotes Microvascular Network Formation.

ABSTRACT: Mechanical interactions between cells and their surrounding extracellular matrix (ECM) guide many fundamental cell behaviors. Native connective tissue consists of highly organized, 3D networks of ECM fibers with complex, nonlinear mechanical properties. The most abundant stromal matrix component is fibrillar type I collagen, which often possesses a wavy, crimped morphology that confers strain- and load-dependent nonlinear mechanical behavior. Here, we established a new and simple method for engineering electrospun fibrous matrices composed of dextran vinyl sulfone (DexVS) with controllable crimped structure. A hydrophilic peptide was functionalized to DexVS matrices to trigger swelling of individual hydrogel fibers, resulting in crimped microstructure due to the fixed anchorage of fibers. Mechanical characterization of these matrices under tension confirmed orthogonal control over nonlinear stress-strain responses and matrix stiffness. We next examined ECM mechanosensing of individual endothelial cells (ECs) and found that fiber crimp promoted physical matrix remodeling alongside decreases in cell spreading, focal adhesion area, and nuclear localization of Yes-associated protein (YAP). These changes corresponded to an increase in migration speed, along with evidence for long-range interactions between neighboring cells in crimped matrices. Interestingly, when ECs were seeded at high density in crimped matrices, capillary-like networks rapidly assembled and contained tube-like cellular structures wrapped around bundles of synthetic matrix fibers due to increased physical reorganization of matrix fibers. Our work provides an additional level of mechanical and architectural tunability to synthetic fibrous matrices and implicates a critical role for mechanical nonlinearity in EC mechanosensing and network formation.

SUBMITTER: Davidson CD

PROVIDER: S-EPMC7580766 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Transwell-based models of the blood-brain barrier (BBB) incorporating monolayers of human brain microvascular endothelial cells (dhBMECs) derived from induced pluripotent stem cells show many of the key features of the BBB, including expression of transporters and efflux pumps, expression of tight junction proteins, and physiological values of transendothelial electrical resistance. The fabrication of 3D BBB models using dhBMECs has so far been unsuccessful due to the poor adhesion and survival of these cells on matrix materials commonly used in tissue engineering.To address this issue, we systematically screened a wide range of matrix materials (collagen I, hyaluronic acid, and fibrin), compositions (laminin/entactin), protein coatings (fibronectin, laminin, collagen IV, perlecan, and agrin), and soluble factors (ROCK inhibitor and cyclic adenosine monophosphate) in 2D culture to assess cell adhesion, spreading, and barrier function.Cell coverage increased with stiffness of collagen I gels coated with collagen IV and fibronectin. On 7 mg mL-1 collagen I gels coated with basement membrane proteins (fibronectin, collagen IV, and laminin), cell coverage was high but did not reliably reach confluence. The transendothelial electrical resistance (TEER) on collagen I gels coated with basement membrane proteins was lower than on coated transwell membranes. Agrin, a heparin sulfate proteoglycan found in basement membranes of the brain, promoted monolayer formation but resulted in a significant decrease in transendothelial electrical resistance (TEER). However, the addition of ROCK inhibitor, cAMP, or cross-linking the gels to increase stiffness, resulted in a significant improvement of TEER values and enabled the formation of confluent monolayers.Having identified matrix compositions that promote monolayer formation and barrier function, we successfully fabricated dhBMEC microvessels in cross-linked collagen I gels coated with fibronectin and collagen IV, and treated with ROCK inhibitor and cAMP. We measured apparent permeability values for Lucifer yellow, comparable to values obtained in the transwell assay. During these experiments we observed no focal leaks, suggesting the formation of tight junctions that effectively block paracellular transport.

Project description:This work developed novel jute-yarn, non-crimp, unidirectional (UD) preforms and their composites, with three different types of warp jute yarns of varying linear densities and twists in the dry UD preforms, in order to present a possible solution to the detrimental effects of higher yarn twists and crimp at the warp-weft yarn interlacements of traditional, woven, preform-based composites on their mechanical properties. In the developed UD preforms, warp jute yarns were placed in parallel by using a wooden picture-frame pin board, with the minimal number of glass weft yarns to avoid crimp at the warp-weft yarns interlacements, which can significantly enhance the load-bearing ability of UD composites compared to traditional, woven, preform composites. It was found that an optimal combination of jute warp yarn linear densities and twists in the UD preforms is important to achieve the best possible mechanical properties of newly developed UD composites, because it encourages a proper polymer-matrix impregnation on jute fibres, leading to excellent fibre-matrix interface bonding. Composites made from the 25 lb/spindle jute warp yarn linear density (UD25) exhibited higher tensile and flexural properties than other UD composites (UD20, UD30). All the UD composites showed a much better performance compared to the traditional woven preform composites (W20), which were obviously related to the higher crimp and yarn interlacements, less load-carrying capacity, and poor fiber-matrix interfaces of W20 composites. UD25 composites exhibited a significant enhancement in tensile modulus by ~232% and strength by ~146%; flexural modulus by 138.5% and strength by 145% compared to W20 composites. This reveals that newly developed, non-crimp, UD preform composites can effectively replace the traditional woven composites in lightweight, load-bearing, complex-shaped composite applications, and hence, this warrants further investigations of the developed composites, especially on long-term and dynamic-loading mechanical characterizations.

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Fiber Crimp Confers Matrix Mechanical Nonlinearity, Regulates Endothelial Cell Mechanosensing, and Promotes Microvascular Network Formation.

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