Steering cell behavior through mechanobiology in 3D: A regenerative medicine perspective

Mechanobiology, translating mechanical signals into biological ones, greatly affects cellular behavior. Steering cellular behavior for cell-based regenerative medicine approaches requires a thorough understanding of the orchestrating molecular mechanisms, among which mechanotransducive ones are being more and more elucidated. Because of their wide use and highly mechanotransduction dependent differentiation, this review focuses on mesenchymal stromal cells (MSCs), while also briefly relating the discussed results to other cell types. While the mechanotransduction pathways are relatively well-studied in 2D, much remains unknown of the role and regulation of these pathways in 3D. Ultimately, cells need to be cultured in a 3D environment to create functional de novo tissue. In this review, we explore the literature on the roles of different material properties on cellular behavior and mechanobiology in 2D and 3D. For example, while stiffness plays a dominant role in 2D MSCs differentiation, it seems to be of subordinate importance in 3D MSCs differentiation, where matrix remodeling seems to be key. Also, the role and regulation of some of the main mechanotransduction players are discussed, focusing on MSCs. We have only just begun to fundamentally understand MSCs and other stem cells behavior in 3D and more fundamental research is required to advance biomaterials able to replicate the stem cell niche and control cell activity. This better understanding will contribute to smarter tissue engineering scaffold design and the advancement of regenerative medicine.