ADGRG1 blockade drives astrocyte positioning into the extracellular matrix to reduce scar size

After the central nervous system (CNS) injury, inflammatory cells enter the lesion core and a fibrotic extracellular matrix accumulates. Astrocytes subsequently cluster around this matrix, forming a glial scar, but the role of the extracellular matrix in scar formation remains poorly understood. Here, we identify type III collagen, a major fibrotic extracellular matrix component after spinal cord injury, as a key regulator of astrocyte behavior. Using single-nucleus transcriptomics, spatial transcriptomics, and time-lapse cell imaging, we show that type III collagen positions astrocytes at the boundary of the fibrotic matrix by activating the adhesion G protein-coupled receptor G1 (ADGRG1) and its downstream effector RhoA. Blocking ADGRG1 genetically or pharmacologically allows astrocytes to enter the fibrotic matrix, resulting in a smaller scar, improved neuronal regeneration, and better motor recovery. The migration of human-induced pluripotent stem cell-derived astrocytes was inhibited by type III collagen via the ADGRG1-RhoA pathway, supporting their therapeutic potential. Our findings reveal the importance of controlling glial scar positioning via the type III collagen-ADGRG1 axis, providing a novel therapeutic target for CNS injury.