Bio-inspired Microenvironments Regulate Cell Fate

Epigenetic regulation of stem cell fate by intrinsic properties of the surrounding extracellular matrix (ECM), e.g. stiffness, organization, composition, etc., appears to be an important yet underappreciated contributor in development, disease, and aging. I will describe our efforts to develop biomimetic environments that mimic key intrinsic ECM properties to assess their contribution to regulating cell fate. For example, pre-cardiac mesodermal cells mature in to adult cardiomyocytes when their matrix mimics the 10-fold increase in stiffness that occurs naturally during development. Adult mesenchymal stem cells (MSCs) are particularly sensitive to small spatial stiffness gradients which can be found naturally in vivo; these gradients induce cell migration prior to differentiation and may in part explain MSC accumulation in stiffer regions of tissue interfaces. However, disease often inhibits these natural processes by creating an ischemic, fibrotic, and/or rigid environment. When matrix stiffness resembles the rigid fibrotic scar, micropatterning cells into specific morphologies can reset the cell to the appropriate contractility level required for myogenesis. Using these finding as design principles, we are engineering nano-patterned diblock copolymer foams to better guide cell differentiation in diseased microenvironments in vivo, but taken together these data at least imply that matrix properties, when displayed at the right time and place, are important regulators of cell fate.