Abstract DP005: Targeting the Brain–Heart Axis: Intranasal Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells for Vascular Dementia with Metabolic Dysfunction

Introduction: The brain–heart axis critically influences outcomes after cerebrovascular disease, yet few therapies target both organs simultaneously. Exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSC-Exos) possess regenerative and immunomodulatory potential, but their efficacy in vascular dementia (VaD) with metabolic dysfunction—particularly for concurrent cardiac injury—remains unknown. This study investigated hUCMSC-Exos as a dual-target therapy for the brain–heart axis in a murine VaD model with metabolic comorbidity. Methods: Male C57BL/6J mice (6–8 months) were fed a high-fat diet (HFD) and subjected to bilateral common carotid artery stenosis (BCAS) to induce VaD with metabolic disturbance. Mice received intranasal hUC-MSC-Exos or vehicle. Cognitive performance, cardiac function (echocardiography), and myocardial histopathology were assessed. Mechanistic analyses included proteomics of hUCMSC-Exos, bulk RNA sequencing of brain and heart, single-cell RNA sequencing (scRNA-seq), RT-PCR, Western blotting, and immunofluorescence. Results: BCAS+HFD mice developed severe cognitive impairment, left ventricular dysfunction, and myocardial fibrosis. hUC-MSC-Exos were enriched in proteins involved in cell junction assembly (ACTG1, THBS1, TLN1), IL-4–mediated immune modulation (HSP90AB1, ARG1), wound healing (COL1A1, SERPINE1), and exocytosis (VAMP7, STX1B). Treatment significantly improved memory performance, restored cardiac contractility, and reduced fibrosis. Brain RNA-seq identified 49 upregulated genes linked to synaptic transmission (Avp, Hcrt, Cartpt) and motor unit remodeling (Tnnc1, Tnni1), alongside downregulation of neuroinflammatory mediators. Cardiac RNA-seq revealed activation of VEGF signaling (Myo1c, Sema6a, Tcf4, Jcad, Spry2), suppression of chemokines (Ccl5, Ccl7, Ccl8), antigen presentation (H2-Aa, H2-D1, Cd74), and normalization of lipid metabolism (downregulation of Acat1, Cidea, Hsd11b1 and Spp1). Conclusion: Intranasal hUC-MSC-Exos provide potent dual neuro-cardiac protection in VaD with metabolic dysfunction, acting through modulation of neurovascular signaling, endothelial repair, inflammation, and metabolism. These findings position hUC-MSC-Exos as a promising strategy for therapeutically targeting the brain–heart axis in complex cerebrovascular–cardiac syndromes.