FIGURE 3.

Self-biophysical transduction for mesenchymal stem cell (MSCs) osteogenesis, including biophysical sensitive ion channels, primary cilium, and biophysical sensitive. When MSCs are exposed to biophysical stimuli, various biophysical sensitive ion channels on the plasma membrane may be activated for the influx of Ca²⁺, which include voltage-gated calcium channels (VGCC), stretch-activated calcium channels (SACCs), Piezo, transient receptor potential vallanoid 1 (TPRV1), and TPRV4. TPRV4 is located at high-strain regions, especially primary cilium. Biophysical stimuli can also stimulate the release of Ca²⁺ from the endoplasmic reticulum to the cytoplasm by uncanonical Wnt-Ca2+ signaling. In specific, Wnt ligand binds to the Frizzled (Fzd)/receptor tyrosine kinase-like orphan receptor (Ror) complex to activate Dishevelled (Dvl), which then activates phospholipase C (PLC) to produce inositol 1,4,5-trisphosphate (IP3). IP3 could activate IP3 receptor for the release of Ca²⁺ from the endoplasmic reticulum. The increased Ca²⁺ in the cytoplasm may promote osteogenic differentiation by activating calcineurin/Nuclear Factor of Activated Cells (NF-AT) signaling and initiating extracellular signal-related kinase 1/2 (ERK1/2) by focal adhesion kinase (FAK) to regulate the activity of β-catenin. Biophysical stimuli could regulate the primary cilium containing intraflagellar transport protein 88 (IFT88) for MSC osteogenesis by regulating length or Gpr161/adenylyl cyclase 6 (AC6) signaling, and the activation of AC6 promotes the synthesis of cyclic adenosine 3′,5′-monophosphate (cAMP), which then promotes the osteogenic differentiation of MSCs by Hedgehog (Hb) signaling and proteinkinase A (PKA) signaling. Biophysical stimuli could also promote some long noncoding RNAs (lncRNAs) to inhibit some microRNAs (miRNAs) for osteogenic differentiation. Created with BioRender.com.