Abstract
The extracellular matrix plays a critical role in orchestrating the events necessary for wound healing, muscle repair, morphogenesis, new blood vessel growth, and cancer invasion. In this study, we investigate the influence of extracellular matrix topography on the coordination of multi-cellular interactions in the context of angiogenesis. To do this, we validate our spatio-temporal mathematical model of angiogenesis against empirical data, and within this framework, we vary the density of the matrix fibers to simulate different tissue environments and to explore the possibility of manipulating the extracellular matrix to achieve pro- and anti-angiogenic effects. The model predicts specific ranges of matrix fiber densities that maximize sprout extension speed, induce branching, or interrupt normal angiogenesis, which are independently confirmed by experiment. We then explore matrix fiber alignment as a key factor contributing to peak sprout velocities and in mediating cell shape and orientation. We also quantify the effects of proteolytic matrix degradation by the tip cell on sprout velocity and demonstrate that degradation promotes sprout growth at high matrix densities, but has an inhibitory effect at lower densities. Our results are discussed in the context of ECM targeted pro- and anti-angiogenic therapies that can be tested empirically.
Highlights
The extracellular matrix (ECM) is a major component of the extravascular tissue region, or stroma, and plays a central role in morphogenesis, including embryogenesis [1], tissue repair and wound healing [2], new blood vessel growth [3], and cancer invasion [4]
How cells interact with the extracellular matrix is important in many processes from wound healing to cancer invasion
We use a computational model to investigate the topography of the matrix on cell migration and coordination in the context of tumor induced new blood vessel growth
Summary
The extracellular matrix (ECM) is a major component of the extravascular tissue region, or stroma, and plays a central role in morphogenesis, including embryogenesis [1], tissue repair and wound healing [2], new blood vessel growth [3], and cancer invasion [4]. A large body of research is concentrated on understanding how cell-ECM interactions impact and regulate morphogenic processes. Results from such investigations illuminate the active role of the ECM in transmitting biochemical signals and mechanical forces that mediate cell survival, phenotype, shape, and orientation. Cells are equipped with and can upregulate transmembrane receptors that enable them to receive signals from and interact with their environment Integrins are one such receptor and are stimulated by the various proteins of the ECM [5,6]. Migratory guidance via focal adhesion binding sites in the ECM is a phenomenon referred to as contact guidance and plays a key role in guiding new vessel growth [9]
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