Pressure-induced mesenchymal stem cell osteogenesis is dependent on intermediate filament remodeling.

Abstract

Macroscale loading of bone generates a complex local mechanical microenvironment that drives osteogenesis and bone mechanoadaptation. One such mechanical stimulus generated is hydrostatic pressure (HP); however, the effect of HP on mesenchymal stem cells (MSCs) and the mechanotransduction mechanisms utilized by these cells to sense this stimulus are yet to be fully elucidated. In this study, we demonstrate that cyclic HP is a potent mediator of cytoskeletal reorganization and increases in osteogenic responses in MSCs. In particular, we demonstrate that the intermediate filament (IF) network undergoes breakdown and reorganization with centripetal translocation of IF bundles toward the perinuclear region. Furthermore, we show for the first time that this IF remodeling is required for loading-induced MSC osteogenesis, revealing a novel mechanism of MSC mechanotransduction. In addition, we demonstrate that chemical disruption of IFs with withaferin A induces a similar mechanism of IF breakdown and remodeling as well as a subsequent increase in osteogenic gene expression in MSCs, exhibiting a potential mechanotherapeutic effect to enhance MSC osteogenesis. This study therefore highlights a novel mechanotransduction mechanism of pressure-induced MSC osteogenesis involving the understudied cytoskeletal structure, the IF, and demonstrates a potential new therapy to enhance bone formation in bone-loss diseases such as osteoporosis.