Andrew Putnam, PhD
Associate Professor, Biomedical Engineering
University of Michigan

The responses of cells to chemical inputs, such as growth factors and hormones, have been widely studied in the cell biology community for decades.  Independently, many investigators in the bioengineering community have focused on the responses of cells and tissues to externally applied mechanical forces.  Increasing evidence suggests that cells are also sensitive to the intrinsic mechanical properties of their microenvironment, specifically the extracellular matrix (ECM), and that these properties can influence tissue patterning and morphogenesis.  However, the impact of ECM mechanics on morphogenesis in 3D remains unclear, due in part to the fact that substrate mechanical properties, adhesion ligand density, and proteolytic sensitivity are intimately linked in native biopolymers systems. To decouple these effects, many research groups (ours included) have explored the use of synthetic hydrogels, based on the argument that their bulk moduli can be tuned independently of changes in biological recognition motifs. However, altering cross-link density to change bulk mechanical properties simultaneously alters the micro- and nanostructure of most hydrogels, which in turn profoundly influences cell shape and macromolecular diffusive transport.  Further complicating interpretations is the fact that the bulk mechanical properties of many systems may change significantly with time, due to either passive hydrolysis, cell-mediated proteolysis, or both. Such biomaterial limitations complicate a predictive understanding of how ECM chemistry and mechanics conspire to influence cell fate in 3D, and thus the ultimate goal of deriving constitutive equations that govern material design for tissue engineering applications remains elusive.  Nevertheless, new methods and tools to measure microscale mechanics on length scales relevant to cells are yielding quantitative insights regarding the influence of cell-generated tractional forces, and the ability of the ECM to resist those forces, on complex cellular processes in 3D.  This talk will focus on this broad topic of the ECM’s mechanical influence on cell fate, with a particular emphasis on the role of the ECM and other microenvironmental cues on the formation of new vasculature.