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bioRxiv · 10.1101/2025.08.20.671398

MiR-23b Neutralization In Brain Endothelium Promotes Blood-Brain Barrier Repair Through Wnt/Beta-catenin Dependent And Independent Mechanisms

Pedersen, I. M.·Martinez, V. A.·Nakanishi, S.·Krog, J. D.·Krog, I. D.·Jury, D.·Lawson, B.·Körbelin, J.·Agalliu, D.
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Abstract

Blood-brain barrier (BBB) disruption drives stroke and other CNS disorders pathology, yet restoring its integrity remains challenging. Using an unbiased anti-miR lentiviral screen, miR-23b was identified as a critical negative regulator of BBB integrity in brain endothelial cells (BECs). Targeted inhibition of miR-23b using anti-miR-23b, validated by Wnt-reporter, Wnt-rescue, and eCLIP analysis, demonstrates that BEC miR-23b silencing in BECs, enhances junctional protein expression and strengthens barrier function while suppressing transcellular transport. Global multi-omics analysis reveals that miR-23b acts as a robust driver of angiogenesis-specific genes and proteins. Conversely, anti-miR-23b induces the expression of factors essential for BBB stabilization and repair. Notably, anti-miR-23b enhances these protective barrier properties through the multi-faceted regulation of Wnt/{beta}-catenin, TGF-{beta}, Notch, and VEGF signaling mechanisms. Using a 3D microfluidic platform, anti-miR-23b was shown to foster BBB repair by accelerating vessel maturation and enhancing resilience against ischemic injury. Proof-of-concept studies show that BEC specific AAVBR1-anti-miR-23b gene therapy reinforces BBB tight junctions, reduces BBB leakage, and improves outcome measures in a transient middle cerebral artery occlusion (t-MCAO) stroke model. Thus, miR-23b is a critical regulator of cerebrovascular integrity, positioning anti-miR-23b as a promising RNA-based therapy to enhance BBB stability and repair in stroke and other CNS disorders.

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Pedersen, I. M., Martinez, V. A., Nakanishi, S., Krog, J. D., Krog, I. D., Jury, D., Lawson, B., Körbelin, J., Agalliu, D.. 2025-08-25. MiR-23b Neutralization In Brain Endothelium Promotes Blood-Brain Barrier Repair Through Wnt/Beta-catenin Dependent And Independent Mechanisms. https://doi.org/10.1101/2025.08.20.671398

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