Tissue-level Mechanosensitivity: Predicting and Controlling the Orientation of 3D Vascular Networks

Understanding the mechanosensitivity of tissues is a fundamentally important problem having far-reaching implications for tissue engineering. Here we study vascular networks formed by a co-culture of fibroblasts and endothelial cells embedded in three-dimensional biomaterials experiencing external, physiologically-relevant forces.

We show that cyclic stretching of the biomaterial orients the newly formed network perpendicularly to the stretching direction, independently of the geometric aspect ratio. A two-dimensional theory explains this observation in terms of the network’s stored elastic energy if the cell-embedded biomaterial features a vanishing effective Poisson’s ratio, which we directly verify. We further show that under static stretch vascular networks orient parallel to the stretching direction due to force-induced anisotropy of the biomaterial polymer network. Additionally, static stretching followed by cyclic stretching reveals a competition between the two mechanosensitive mechanisms.

Furthermore, The two cell types show distinctly different sensitivities to mechanical stimulation. The fibroblasts, sense the stress directly and respond by increased alignment, proliferation, differentiation, and migration, facilitated by YAP translocation into the nucleus. In contrast, the endothelial cells form aligned vessels by tracking fibroblast alignment.

These results demonstrate tissue-level mechanosensitivity and constitute an essential step toward developing enhanced tissue repair capabilities using well-oriented vascular networks.