Subcutaneous transplantation of lung organoids ameliorates vascular dementia via the IGFBP7-Ago2 mediated lung-brain axis.

Vascular dementia (VaD), whose leading cause is chronic cerebral hypoperfusion (CCH), currently has no approved effective disease-modifying therapies. The lung-brain axis mediates crosstalk between the lung and the nervous system, yet the specific mediators underlying its role in VaD remain unclear. This study demonstrated that subcutaneous transplantation of lung organoids (LO) ameliorated cognitive dysfunction in a mouse model of bilateral common carotid artery stenosis (BCAS). We showed that BCAS-induced CCH downregulated pulmonary expression of insulin-like growth factor-binding protein 7 (IGFBP7), a key mediator of the lung-brain axis. LO transplantation restored​circulating IGFBP7, which translocated to the brain and acted directly on microglia by binding to Argonaute2 (Ago2), thereby inhibiting pro-inflammatory signaling pathways, reducing neurovascular damage and neuroinflammation, and alleviating​peripheral lung injury caused by CCH. Notably, LO transplantation concurrently restores cerebral function and pulmonary homeostasis, with concurrent recovery of endogenous pulmonary IGFBP7 expression in BCAS mice, indicating concurrent improvement of both brain and lung pathology through lung-brain axis crosstalk. This study confirmed that LO transplantation represented an effective biotherapy for VaD and identified the IGFBP7-Ago2 axis as a core regulatory pathway of the lung-brain axis. These findings provide mechanistic insights into the pathogenesis of VaD and highlight that IGFBP7 is a potential therapeutic target for restoring inter-organ crosstalk in dementia.