Regulation of angiogenesis by the extracellular matrix

A major challenge in the field of tissue engineering is the generation of new materials that can support angiogenesis, wherein endothelial cells from existing vasculature invade the surrounding matrix to form new blood vessels. This is largely due to a gap in our understanding of how extracellular matrix (ECM) properties affect angiogenic sprouting and ultimately, blood vessel formation. Due to the complex nature of native ECMs, it is difficult to identify the role of individual matrix properties. Here, it is our aim to make use of synthetic hydrogels with independently tunable properties to determine how the ECM regulates angiogenesis.

In addition to ECM properties, its architecture also plays a key role in angiogenesis, segregating cell populations and defining fluid versus solid domains. To recapitulate such features, hydrogel materials that are amenable to precision molding are vital tools to accurately defining tissue architecture. However, most existing synthetic hydrogel systems are difficult to precision mold due to the swelling of the material that occurs upon equilibrium hydration. To overcome this challenge, we developed a non-swelling dextran-based hydrogel with the ability to incorporate other bioactive features essential to controlling cell behavior (in particular the cell adhesive peptide motif RGD, MMP cleavable crosslinks). We then integrated the hydrogels into a microfluidic platform consisting of molded tubular channels that are seeded with endothelial cells and subjected to chemokine gradients to induce angiogenic sprouting (Trappmann et al., Nature Communications 2017).

Mesenchymal stem cell fate in 3D environments

Mesenchymal stem cells (MSCs) are of great interest for tissue engineering applications, as they can easily differentiate into multiple lineages. While it has been shown that the stiffness of the 2D culture substrate is an important regulator of MSC fate, it is not at all understood how MSC mechanosensing occurs in more natural 3D environments. To understand how MSC spreading, proliferation and differentiation are regulated by 3D matrix stiffness, we make use of synthetic hydrogels with tunable adhesiveness, as well as mechanical and degradative properties.

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