TRPV4-mediated calcium signaling in mesenchymal stem cells regulates aligned collagen matrix formation and vinculin tension

Significance The development, repair, and regeneration of anisotropic connective tissues (e.g., tendon, ligament, meniscus) involve deposition of aligned fibrillar collagen by cells. However, the intracellular signaling mechanisms mediating this process are not fully understood. We show that the mechanosensitive cation channel transient receptor potential vanilloid 4 (TRPV4) plays a critical role in controlling aligned collagen assembly by mesenchymal stem cells. Specifically, inhibiting TRPV4 activity in mesenchymal stem cells disrupts aligned collagen matrix assembly, and conversely, activating TRPV4 accelerates collagen deposition. Additionally, TRVP4 activity modulates force transmitted across vinculin, a key mechanosensitive protein within cell–matrix adhesions, where cell-generated forces are critical in fibrillar collagen assembly. Understanding and controlling specific cell-signaling mechanisms underlying aligned matrix assembly could lead to improved tissue regeneration outcomes.