Abstract
Mechanical loads are fundamental regulators of bone formation and remodeling. However, the molecular regulation of mechanotransduction during vertebral laminae regeneration remains poorly understood. Here, we found that cerebrospinal fluid pulsation (CSFP) stress—cyclic pulsation stress—could promote the osteogenic and angiogenic abilities of rat mesenchymal stromal cells (MSC), thereby promoting tissue-engineered laminae’s bone and blood vessel formation. In the process, F-actin relayed CSFP stress to promote the nuclear translocation of YAP1, which then decreased the degradation and promoted the nuclear translocation of β-Catenin. In turn, the nuclear translocation of β-Catenin promoted the osteogenic differentiation and angiogenic abilities of MSC, thereby promoting tissue-engineered laminae’s bone and blood vessel formation. Thus, we conclude that CSFP promotes the osteogenesis and angiogenesis of tissue-engineered laminae through the F-actin/YAP-1/β-Catenin signaling axis. This study advances our understanding of vertebral laminae regeneration and provides potential therapeutic approaches for spinal degeneration after spinal laminectomy.
Highlights
Mechanical forces are part of environmental cues that are sensed and responded to during bone development and regeneration[1,2].Apart from the complex networks of biochemical signaling that direct the differentiation during bone formation, bone cells can constantly respond to mechanical cues such as hydraulic pressure, fluid shear stress, pulsation stress, or substrate stiffness from the microenvironment[2,3,4,5]
Immunofluorescent staining revealed that the expression and localization trends of β-Catenin and Osterix were consistent, and the Pearson’s correlation value analyzed by ImageJ was about 0.97, indicating a strong positive correlation between β-Catenin and osteoblast differentiation (Fig. 6). These results suggested that cerebrospinal fluid pulsation (CSFP) could promote the expression levels of osteogenic and angiogenic markers, thereby promoting the bone and blood vessel formation of tissue-engineered laminae (TEL) through the regulation of β-Catenin
Knockdown, and inhibition studies, we found that CSFP promoted the expression and nuclear translocation of β-Catenin to promote osteogenic and angiogenic abilities of mesenchymal stromal cells (MSC), thereby the bone and blood vessel formation of TEL
Summary
Apart from the complex networks of biochemical signaling that direct the differentiation during bone formation, bone cells can constantly respond to mechanical cues such as hydraulic pressure, fluid shear stress, pulsation stress, or substrate stiffness from the microenvironment[2,3,4,5]. Mechanotransduction, the conversion of mechanical forces into biological signals, is a fundamental physiologic process critical for bone formation[6,7]. TRPV4 mediates fluid shear stress-induced calcium signaling and early osteogenic differentiation in bone mesenchymal stem cells[13]. Piezo1/2 can relay fluid shear stress to activate Ca2+ influx to promote concerted activation of NFATc1, YAP1, and β-Catenin transcription factors by inducing their dephosphorylation as well as NFAT/YAP1/β-Catenin complex formation[5,14]
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