High‐mobility group box 1 from reactive astrocytes enhances the accumulation of endothelial progenitor cells in damaged white matter

High‐mobility group box 1 ( HMGB 1) was initially described as a damage‐associated‐molecular‐pattern ( DAMP ) mediator that worsens acute brain injury after stroke. But, recent findings suggest that HMGB 1 can play a surprisingly beneficial role during stroke recovery by promoting endothelial progenitor cell ( EPC ) function and vascular remodeling in cortical gray matter. Here, we ask whether HMGB 1 may also influence EPC responses in white matter injury. The standard lysophosphatidylcholine ( LPC ) injection model was used to induce focal demyelination in the corpus callosum of mice. Immunostaining showed that within the focal white matter lesions, HMGB 1 was up‐regulated in GFAP ‐positive reactive astrocytes, along with the accumulation of Flk1/ CD 34‐double‐positive EPC s that expressed pro‐recovery mediators such as brain‐derived neurotrophic factor and basic fibroblast growth factor. Astrocyte– EPC signaling required the HMGB 1 receptor RAGE as treatment with RAGE ‐neutralizing antibody significantly decreased EPC accumulation. Moreover, suppression of HMGB 1 with si RNA in vivo significantly decreased EPC numbers in damaged white matter as well as proliferated endothelial cell numbers. Finally, in vitro cell culture systems confirmed that HMGB 1 directly affected EPC function such as migration and tube formation. Taken together, our findings suggest that HMGB 1 from reactive astrocytes may attract EPC s to promote recovery after white matter injury.