Hepcidin depending on astrocytic NEO1 ameliorates blood-brain barrier dysfunction after subarachnoid hemorrhage

• Published in: Cell death & disease Vol. 15; no. 8; pp. 569 - 16
• Main Authors: Wei, Boyang, Liu, Wenchao, Jin, Lei, Huang, Yaxian, Cheng, Wenping, Fan, Haiyan, Su, Shixing, Jin, Fa, Zhang, Xin, Yang, Zeyu, Liang, Shuyin, Li, Longxiang, Wu, Yu, Liu, Yanchao, Duan, Chuanzhi, Li, Xifeng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.08.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 101/58; 13/1; 13/109; 14/19; 14/28; 14/32; 631/378/1341; 64/110; 692/308/575; 692/699/375/534; 96/2; Animal models; Animals; Antibodies; Astrocytes - metabolism; Biochemistry; Biomedical and Life Sciences; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; CD31 antigen; Cell Biology; Cell Culture; Cerebrospinal fluid; Cortex (parietal); Dextran; Disease Models, Animal; Endothelial cells; Endothelial Cells - metabolism; Female; Hepcidin; Hepcidins - genetics; Hepcidins - metabolism; Homeostasis; Humans; Immunology; Life Sciences; Male; Membrane permeability; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Middle Aged; Proteomics; Recovery (Medical); Structure-function relationships; Subarachnoid hemorrhage; Subarachnoid Hemorrhage - metabolism; Transmission electron microscopy
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06909-x

Subarachnoid hemorrhage (SAH) significantly compromises the blood-brain barrier (BBB) and impairs patient recovery. This study elucidates the critical role of astrocytic Neogenin-1 (NEO1) in BBB integrity post-SAH and examines the regulatory effects of hepcidin on endothelial cell (EC) function amid NEO1-mediated disruptions in iron homeostasis. Proteomic analyses of cerebrospinal fluid (CSF) from SAH patients revealed a substantial decrease in NEO1 expression, identifying it as a key factor in BBB integrity. 111 CSF proteins were significantly reduced in early SAH stages (days 1–3), with NEO1 among the most significantly altered. This dysregulation was linked to poorer patient outcomes, as indicated by a negative correlation between NEO1 levels and Modified Rankin Scale scores six months post-SAH ( R  = −0.4743, P  < 0.0001). Experimental models further highlighted the importance of NEO1: SAH model and NEO1 GFAP-Cre mice exhibited exacerbated EC dysfunction and increased BBB permeability, evidenced by significant Evans Blue retention and dextran leakage in the parietal cortex, effects that were mitigated by hepcidin administration. Our findings highlight the complex interplay between astrocytic signaling and endothelial function in SAH pathophysiology. The loss of astrocytic NEO1 led to increased EC proliferation and altered BBB structure, as confirmed by transmission electron microscopy and immunostaining for PECAM-1, indicating heightened blood vessel density in the affected cortex. Hepcidin treatment effectively reversed the EC dysfunction and BBB disruption in both NEO1-cKO mice and the SAH model, highlighting its potential as a therapeutic agent to enhance recovery and improve prognosis following SAH.