Chirality Controls Mesenchymal Stem Cell Lineage Diversification through Mechanoresponses

Biogenesis and tissue development are based on the heterogenesis of multipotent stem cells. However, the underlying mechanisms of stem cell fate specification are unclear. Chirality is one of the most crucial factors that affects stem cell development and is implicated in asymmetrical cell morphology formation; however, its function in heterogeneous cell fate determination remains elusive. In this study, it is reported that the chirality of a constructed 3D extracellular matrix (ECM) differentiates mesenchymal stem cells to diverse lineages of osteogenic and adipogenic cells by providing primary heterogeneity. Molecular analysis shows that left‐handed chirality of the ECM enhances the clustering of the mechanosensor Itgα5, while right‐handed chirality decreases this effect. These differential adhesion patterns further activate distinct mechanotransduction events involving the contractile state, focal adhesion kinase/extracellular signal‐regulated kinase 1/2 cascades, and yes‐associated protein/runt‐related transcription factor 2 nuclear translocation, which direct heterogeneous differentiation. Moreover, theoretical modeling demonstrates that diverse chirality mechanosensing is initiated by biphasic modes of fibronectin tethering. The findings of chirality‐dependent lineage specification of stem cells provide potential strategies for the biogenesis of organisms and regenerative therapies. The chirality of a constructed 3D extracellular matrix is capable of controlling mesenchymal stem cell (MSC) lineage diversification in vitro and in vivo. The chirality provides primary heterogeneity to initiate biphasic fibronectin tethering, which induces significant alterations in mechanosensing and mechanotransduction to specify stem cell lineages of osteogenesis or adipogenesis. The findings present potential strategies for the biogenesis and regeneration.