Mechanosensitive Piezo1 is crucial for periosteal stem cell-mediated fracture healing

Abstract

The biomechanical environment plays a dominant role in fracture healing, and Piezo1 is regarded as a major mechanosensor in bone homeostasis. However, the role of Piezo1 in fracture healing is not yet well characterized. In this study, we first delineated that Piezo1 is highly expressed in periosteal stem cells (PSCs) and their derived osteoblastic lineage cells and chondrocytes. Furthermore, downregulation of Piezo1 in callus leads to impaired fracture healing, while activation by its specific agonist promotes fracture healing through stimulation of PSC-modulated chondrogenesis and osteogenesis, along with accelerated cartilage-to-bone transformation. Interestingly, vascular endothelial growth factor A is upregulated after Yoda1 treatment of PSCs, indicating an indirect role of Piezo1 in angiogenesis. Mechanistically, activation of Piezo1 promotes expression of Yes-associated protein (YAP) and its nuclear localization in PSCs, which in turn increases the expression and nuclear localization of β-catenin. In detail, YAP directly interacts with β-catenin in the nucleus and forms a transcriptional YAP/β-catenin complex, which upregulates osteogenic, chondrogenic and angiogenic factors. Lastly, Yoda1 treatment significantly improves fracture healing in a delayed union mouse model generated by tail suspension. These findings indicate that Piezo1 is a potential therapeutic target for fracture delayed union or nonunion.

Synergistic Effect of Magneto-Mechanical Bioengineered Stem Cells and Magnetic Field to Alleviate Osteoporosis

“…Osteogenesis and vascularization are intimately coupled during bone regeneration, and the reconstruction of blood flow provides nutritional support for bone injury repair. , It has been reported that both angiogenesis and osteogenesis are regulated by cellular mechanical stress . The angiogenic ability of the MSNPs with magnetic signals was investigated via tube formation assay with human umbilical vein endothelial cells (HUVECs).…”

“…39,40 It has been reported that both angiogenesis and osteogenesis are regulated by cellular mechanical stress. 41 The angiogenic ability of the MSNPs with magnetic signals was investigated via tube formation assay with human umbilical vein endothelial cells (HUVECs). As shown in Figure 4A, magneto-mechanical effects increase blood vessel formation.…”

Accelerated Bone Reconstruction by the Yoda1 Bilayer Membrane via Promotion of Osteointegration and Angiogenesis

“…They found that Yoda1 could improve delayed fracture healing caused by mechanical unloading and increase the bone mass. [ 17,38 ] However, there were significant differences in the injection dose of Yoda1, ranging from 5 µmol kg −1 to 5 mmol kg −1 . A toxic concentration of Yoda1 can be quickly achieved by injecting Yoda1 alone.…”

Three-Dimensional Matrix Stiffness Activates the Piezo1-AMPK-Autophagy Axis to Regulate the Cellular Osteogenic Differentiation

“…Piezo1 is a mechanosensitive ion channel, which is widely expressed in epithelial cells, stem cells, , and cardiomyocytes . It senses extracellular mechanical stimuli and translates them into intracellular biochemical signals, which is involved in various physiological functions of cells. , Previous studies have reported that Piezo1 plays a critical role in maintaining bone homeostasis and that mice specifically knocked out of Piezo1 in osteoblasts usually have hypogenetic development. , Furthermore, hindlimb suspension mice and cellular rotation system osteoblasts suggested that mechanical unloading can inhibit Piezo1 expression, resulting in dysfunctional osteoblasts and bone formation. , Also, Piezo1 was required to adapt to external mechanical fluid shear stress in MC3T3-E1 cells, which induced RUNX2 gene expression .…”