Muscle lineage switching by migratory behaviour-driven epigenetic modifications of human mesenchymal stem cells on a...

Understanding of the fundamental mechanisms of epigenetic modification in the migration of human mesenchymal stem cells (hMSCs) provides surface design strategies for controlling self-renewal and lineage commitment. We investigated the mechanism underlying muscle lineage switching of hMSCs by cellular and nuclear deformation during cell migration on polyamidoamine dendrimer surfaces. With an increase in the dendrimer generation number, cells exhibited increased nuclear deformation and decreased lamin A/C and lamin B1 expression. Analysis of two repressive modifications (H3K9me3 and H3K27me3) and one activating modification (H3K9ac) revealed that H3K9me3 was suppressed, and H3K9ac and H3K27me3 were upregulated in the cultures on a higher-generation dendrimer surface. This induced significant hMSC lineage switching to smooth, skeletal, and cardiac muscle lineages. Thus, reorganizations of the nuclear lamina and cytoskeleton related to migration changes on dendrimer surfaces are responsible for the integrated regulation of histone modifications in hMSCs, thereby shifting the cells from the multipotent state to muscle lineages. These findings improve our understanding of the role of epigenetic modification in cell migration and provide new insights into how designed surfaces can be applied as cell-instructive materials in the field of biomaterial-guided differentiation of hMSCs to different cell types. STATEMENT OF SIGNIFICANCE: Stem cell engineering strategies currently applied the mechanical cues that emerge from cellular microenvironment to regulate stem cell behaviour. This study significantly improved our understanding of the mechanotransduction mechanism involving cell-ECM and cytoskeleton-nucleoskeleton interactions, and of nuclear genome regulation based on cellular responses to biomaterial modifications. The new insights into how the physical environment on a culture surface influences cell behaviour improve our understanding of mechanical control mechanisms of the interactions of cells with the extracellular environment. Our findings are also expected to contribute to and play an essential role in the development of future material strategies for creating artificial cell-instructive niches.