Extended Data Fig. 4: Schematic for the proposed hypothetical model of the mechanisms underlying the efficacy of UDC.

In hemorrhagic stroke, aquaporin expression and disease-associated microglial states are promoted (Fig. 4). Disease-associated microglia inhibit the polarization of aquaporins to astrocytic endfeet⁷⁵. UDC acts principally via mechanosensitive ion channel activation (Fig. 6) and potentially also via direct mechanical fluid compartmental intermixing (Extended Data Fig. 1)²⁵. Via mechanosensitive ion channel activation, UDC shifts microglia from the disease-associated to the homeostatic state (Figs. 4, 5, 6), in accord with prior literature^18,19,20. This microglial phenotypic shift yields increased RBC phagocytosis (Fig. 5) and disinhibition of astrocytic endfeet aquaporin polarization (Figs. 4, 5). The combination of these effects (increased mechanical fluid mixing, aquaporin polarization, and debris phagocytosis) allows for clearance of brain injury debris via the meningeal lymphatics to the cervical lymph nodes (Fig. 1) and possibly – though less directly supported in our presented data – via arachnoid villi to the dural venous sinuses.