A shared extracellular plasticity program drives brain repair and tumor progression

<jats:p>Injury induces complex multicellular repair responses that restore tissue integrity and replenish lost cells. In the brain, regeneration is limited and depends on the proliferation of neural and glial progenitors. But how these cells remodel the microenvironment to support repair remains poorly understood. Here, we profile dividing cells in the injured fruit fly brain revealing signatures of neural stem cell activation and ECM remodeling. We find that rapid activation of a Heparan Sulfate-binding factor (Hpsl) and changes in glypicans condition the extracellular space for proliferation. Hpsl promotes signalling of scarce Dpp/BMP ligands in brain cells with latent proliferative capacity and regulates organismal resilience to brain injury. We further show that malignant cells in fly and mouse brains promote similar HS-interactions to support tumor progression. Together, our findings identify extracellular proteoglycan remodeling as a key regulator of brain repair and uncover a common plasticity program engaged by brain damage and tumorigenesis.</jats:p>