APOE3基督城变体增强iPSC衍生间充质基质细胞的神经血管支持功能
APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells.
摘要(中文译文)
衰老和神经退行性疾病（如阿尔茨海默病，AD）与血脑屏障（BBB）和神经血管单元（NVU）的进行性功能障碍相关，导致血管完整性受损和神经元易损性增加。载脂蛋白E（APOE）是神经血管功能的关键调节因子，罕见的“基督城”变异体（APOE Christchurch）对AD具有保护作用。间充质基质细胞（MSC）因其对血管和神经细胞的旁分泌作用，是治疗神经退行性疾病的一种有前景的细胞疗法。为研究APOE Christchurch如何影响MSC介导的神经血管支持，我们使用了携带纯合APOE Christchurch或APOE3的同基因iPSC来源的MSC（iMSC）。我们发现，APOE Christchurch iMSC对LPS诱导的THP1细胞NFκB活化具有更强的免疫抑制作用。与内皮细胞直接共培养时，APOE Christchurch iMSC还增强了内皮屏障电阻和血管生成能力，优于APOE3 iMSC。此外，APOE Christchurch iMSC的条件培养基比APOE3 iMSC的条件培养基更有效地促进神经突生长。代谢谱分析揭示了APOE Christchurch与APOE3 iMSC之间的差异，提示代谢韧性发生了改变。总之，这些发现表明iMSC通过旁分泌机制支持血管和神经功能，并提示APOE Christchurch变异体改善了MSC介导的神经血管支持的特定方面。这项工作凸显了将基于MSC的疗法与保护性APOE变异体相结合以靶向衰老和神经退行性变中BBB和NVU功能障碍的潜力。
Abstract
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 "Christchurch" variant () 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 influences MSC-mediated neurovascular support, we used isogenic iPSC-derived MSCs (iMSCs) with homozygous or . We found that iMSCs have stronger immunosuppressive effect on LPS-induced NFκB activation of THP1 cells. iMSCs also enhanced endothelial barrier resistance and angiogenic capacity compared to iMSCs when directly co-cultured with endothelial cells. In addition, conditioned medium from iMSCs promoted neurite outgrowth more efficiently than that from iMSCs. Metabolic profiling revealed differences between and iMSCs, suggesting altered metabolic resilience. Together, these findings demonstrate that iMSCs support vascular and neuronal function through paracrine mechanisms and suggest that variant improves specific aspects of MSC-mediated neurovascular support. This work highlights the potential of combining MSC-based therapies with protective variants to target BBB and NVU dysfunction in aging and neurodegeneration.
如何引用
AMA
Paula J Rodriguez Martinez, Aria R Yslas, Yasuteru Inoue, Tammee M Parsons, Samantha K Baker, Wenyan Lu, et al. APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells.. Frontiers in molecular biosciences. 2026; doi:10.3389/fmolb.2026.1778856.
APA
Paula J Rodriguez Martinez, Aria R Yslas, Yasuteru Inoue, Tammee M Parsons, Samantha K Baker, Wenyan Lu, et al (2026). APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells.. Frontiers in molecular biosciences. https://doi.org/10.3389/fmolb.2026.1778856
GB/T 7714
Paula J Rodriguez Martinez, Aria R Yslas, Yasuteru Inoue, Tammee M Parsons, Samantha K Baker, Wenyan Lu, et al. APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells.[J]. Frontiers in molecular biosciences, 2026 doi:10.3389/fmolb.2026.1778856.
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