Fluid shear stress promotes osteogenesis of bone mesenchymal stem cells at early matrix maturity phase through Lamin A/ METTL3 signal axis

During the construction of tissue-engineered bone in vitro, bionic mechanical stimulation has been considered to be critical to cellular response and bone tissue formation. Bone mesenchymal stem cells (BMSCs) at different osteogenesis phases in the bone marrow cavity are subjected to fluid shear stress (FSS). However, the responses of BMSCs at different phases of osteogenic differentiation to FSS remain unknown. Therefore, FSS was applied to BMSCs at different osteogenesis phases in vitro by parallel plate flow chamber, and the osteogenic ability and relaed underlying mechanisms were explored. Our study showed that BMSCs underwent rapid proliferation, early matrix maturity and late mineralization phases at 1, 7 and 14 days of osteogenic induction, respectively. FSS significantly promoted the osteogenic differentiation of BMSCs at early matrix maturation phase. Applying FSS on BMSCs at early matrix maturity phase resulted in significant remodeling of F-actin, forming of stress fibers, and the transduction of mechanical signal by the cytoskeleton-Lamin A pathway. Through the interaction between Lamin A and Methyltransferase-like 3 (METTL3), the levels of METTL3 protein and the m6A methylation genes were increased, promoting the osteoblastic differentiation of BMSCs. The results provided a new insight into the construction of bone tissue in vitro and the treatment strategy for bone defects.