Molecular and mechanical regulators of mesenchymal stem cell microenvironments
McAndrews, Kathleen M.
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Mesenchymal stem cells (MSCs) are multipotent cells that are recruited to sites of inflammation, where they interact with the microenvironment to induce tissue regeneration. As a result, MSCs have shown promise clinically as candidates for tissue engineering and therapeutic targets; however, implementation in the clinic has been limited by an incomplete understanding of how mechanical and chemical cues provided by the microenvironment influence MSC behavior. We first show how molecular cues change the intracellular mechanical properties of differentiating MSCs. We then developed 3D gelatin scaffolds for the expansion and differentiation of MSCs. We found that the composition of the scaffold dictated whether the mechanical or architectural properties directed MSC differentiation. In addition to aiding in tissue regeneration, MSCs are also recruited to tumors, where they interact with the tumor microenvironment to promote metastasis. We sought to elucidate if MSCs are differentially adherent, and potentially recruited more frequently, to metastatic versus nonmetastatic tumors. We found that MSCs are more adherent to metastatic cancer cells and this response can be reversed by blocking the adhesion molecule cadherin 11. Finally, we utilized a 3D coculture model to determine how interactions between metastatic cancer cells and MSCs influence cancer cell invasion. Coculture with MSCs induced directional migration in cancer cells that was dependent on transforming growth factor β (TGF-β) and downstream mechanosensitive pathways. These studies elucidate how MSCs interact with their environment and may have important implications in biomaterial design and the development of cancer therapeutics.