Mechanics Guides Stem Cell Fate via Cytoskeleton Structure

The mechanical properties of microenvironments in our body vary over a broad range and are as important to cells as traditional biochemical cues. An especially striking experiment of this mechano-sensitivity demonstrated that systematic variation of the Young’s elastic modulus E of the substrate can direct the lineage differentiation of human mesenchymal stem cells (hMSCs).
To elucidate the complex interplay of physical and biochemical mechanisms of cellular mechano-sensing, well-defined extracellular matrix (ECM) models are essential. While elastic substrates made of poly-acrylamide (PA) are widely in use, they have the potential drawback that the precursors are cytotoxic and therefore do not allow for 3D culture systems. Here, a novel biomimetic ECM model based on hyaluronic acid (HA) was successfully established that exhibits a widely tuneable and well-defined elasticity E, enables 2D and 3D cell culture and enables us to mimic a variety of distinct in vivo microenvironments. Quantitative analysis of the structure of acto-myosin fibers of hMSCs on elastic substrates with an order parameter S, reveals that the stress fiber morphology is an early morphological marker of mechano-guided differentiation and can be understood using a classical mechanics model. Furthermore, the cytoskeleton also dictates the shape of the nucleus and lends support to a direct mechanical matrix-myosin-nucleus pathway.