Betacellulin promotes post-ischemic brain repair in preclinical stroke models

Introduction Stroke is a leading cause of disability with no restorative treatments beyond the acute phase. Secretome-based strategies offer an alternative to cell therapies (1), Betacellulin (BTC), a growth factor from the endothelial secretome, promotes neural stem cell activation, neurogenesis, and angiogenesis in preclinical settings (2). Its defined nature and paracrine action make it a strong candidate for regenerative therapy. Purpose To evaluate the therapeutic potential of betacellulin as a post-ischemic regenerative treatment in preclinical models of ischemic stroke. Methods Adult mice underwent middle cerebral artery occlusion (MCAO) and received recombinant BTC via intranasal or using osmotic minipump for 5–7 days post-stroke (3,4). Outcomes included neural stem/progenitor cell activation, angiogenesis, infarct reduction, and behavioral testing. Mechanistic studies focused on BTC-induced ErbB1/ErbB4 receptor activation. Toxicity assessments included in vitro human cell studies and in vivo monitoring for adverse responses. This study has followed the "Principles of laboratory animal care". Results BTC significantly increased neurogenic markers (BrdU+, Sox2+) in neurogenic niches (SVZ, DG) and enhanced NeuN+ and Olig2+ populations in injured areas (3). Infarct size was reduced, and angiogenesis stimulated. Behavioral recovery was improved in locomotor and sensory-motor tests. Mechanistically, BTC activates ErbB receptors without disrupting niche integrity. Its effects are reproducible across delivery routes and sexes, with no observed toxicity. BTC stands out for its safety, scalability, and defined mechanism, addressing barriers in secretome translation (1). Conclusions BTC enhances neural repair and functional recovery post-stroke through safe, non-invasive administration. Acting via physiological pathways, BTC is highly suitable for translational development as a regenerative, secretome-derived therapy. BTC is the first defined secretome protein to safely restore neural function post-stroke through non-invasive delivery. BTC could redefine post-stroke therapy, prolonging treatment windows and validating secretome-based regenerative medicine.