Fibroblasts repair blood-brain barrier damage and hemorrhagic brain injury via TIMP2

The function of fibroblasts in intracerebral hemorrhage (ICH) remains elusive. By targeting Col1a1, a fibro-blast-specific marker, we generate mice with ablated Col1a1+ fibroblasts. These mutants show exacer-bated blood-brain barrier (BBB) damage, enlarged injury volume, and worse neurological function, high-lighting a beneficial role of Col1a1+ fibroblasts in ICH. Echoing these findings, fibroblasts significantly decrease endothelial permeability in an in vitro ICH model. Next, we demonstrate that fibroblasts promote BBB integrity in ICH mainly via up-regulating tight junction proteins without affecting transcytosis-associ-ated proteins, indicating a paracellular rather than transcellular mechanism. A subsequent mechanistic study reveals that the BBB-protective effect of fibroblasts is partially mediated by TIMP metallopeptidase inhibitor 2 (TIMP2). Furthermore, we find that exogenous TIMP2 attenuates BBB disruption in these mu-tants after ICH. These results suggest that Col1a1+ fibroblasts repair BBB damage in ICH via the paracel-lular pathway in a TIMP2-dependent manner, and that Col1a1+ fibroblasts and TIMP2 may be targeted in ICH treatment.