Mechanics Regulate Stem Cell Differentiation and Tissue Development

Engineering functional tissues and organs from stem cells requires simultaneous control over both cell fate and organization of tissue architecture. Cell-generated forces, such as cytoskeletal contractility, traction stresses, and cell-cell tension have long been recognized as critical drivers of tissue morphogenesis; nevertheless, it has remained unclear whether these physical forces also directly regulate cell fate decisions by modulating biochemical signaling pathways. In this work, we demonstrated that human embryonic stem cells (hESCs) cultured on compliant engineered substrates self-organize to form discrete gastrulation nodes that foster mesoderm specification. We identified a mechanism whereby localized high cell-adhesion tension induces mesoderm specification by enhancing Wnt/β-catenin signaling, and furthermore, we showed that application of mechanical tension via stretching is sufficient to induce mesoderm specification. Additionally, we demonstrated that cell adhesion proteins and regulators of cytoskeletal contractility control pattern formation in human induced pluripotent stem cells (hiPSCs), independent of cell fate specification. Further, we discovered that a specific Wnt ligand from the niche regulates muscle stem cell (SC) quiescence via Rho signaling that promotes SC contractility. Finally, we developed a novel protocol for performing atomic force microscopy (AFM) on mouse bone marrow to enable characterization of the biophysical properties of the hematopoietic stem cell (HSC) niche. Together, these findings underscore the interplay between tissue organization, cell-generated forces, and morphogen-dependent differentiation. This body of work demonstrates that mechanical forces play a direct role in cell fate specification during development and regulate stem cell function in the adult organism