APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells.

Aging and neurodegenerative disorders like Alzheimer's Disease (AD) are associated with progressive dysfunction of the blood-brain barrier (BBB) and neurovascular unit (NVU), contributing to impaired vascular integrity and neuronal vulnerability. Apolipoprotein E (APOE) is a key regulator of neurovascular function, and the rare APOE3-R136S "Christchurch" variant (APOE3Ch) confers protection against AD. Mesenchymal stromal cells (MSCs) represent a promising cell-based therapy for the treatment of neurodegenerative diseases due to their paracrine effect exerted on vascular and neural cells. To investigate how APOE3Ch influences MSC-mediated neurovascular support, we used isogenic iPSC-derived MSCs (iMSCs) with homozygous APOE3Ch or APOE3. We found that APOE3Ch iMSCs have stronger immunosuppressive effect on LPS-induced NFκB activation of THP1 cells. APOE3Ch iMSCs also enhanced endothelial barrier resistance and angiogenic capacity compared to APOE3 iMSCs when directly co-cultured with endothelial cells. In addition, conditioned medium from APOE3Ch iMSCs promoted neurite outgrowth more efficiently than that from APOE3 iMSCs. Metabolic profiling revealed differences between APOE3Ch and APOE3 iMSCs, suggesting altered metabolic resilience. Together, these findings demonstrate that iMSCs support vascular and neuronal function through paracrine mechanisms and suggest that APOE3Ch variant improves specific aspects of MSC-mediated neurovascular support. This work highlights the potential of combining MSC-based therapies with protective APOE variants to target BBB and NVU dysfunction in aging and neurodegeneration.