Cheung Christine, Goh Yeek Teck, Zhang Jingxian, Wu Chenghan, Guccione Ernesto
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Singapore 119228, Singapore.
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
Cell Rep. 2014 Oct 9;9(1):391-401. doi: 10.1016/j.celrep.2014.08.065. Epub 2014 Oct 2.
There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (Aβ) accumulation is evident in a majority of aged people and patients with cerebral amyloid angiopathy. Here, we leverage human pluripotent stem cells to generate vascular smooth muscle cells (SMCs) from neural crest progenitors, recapitulating brain-vasculature-specific attributes of Aβ metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural-crest-derived SMCs to mediate Aβ uptake and intracellular lysosomal degradation. Hypoxia significantly compromises the contribution of SMCs to Aβ clearance by suppressing LRP1 expression. This enabled us to develop an assay of Aβ uptake by using the neural crest-derived SMCs with hypoxia as a stress paradigm. We then tested several vascular protective compounds in a high-throughput format, demonstrating the value of stem-cell-based phenotypic screening for novel therapeutics and drug repurposing, aimed at alleviating amyloid burden.
人们越来越认识到脑血管对神经退行性疾病的影响。在脑动脉壁中，淀粉样β蛋白（Aβ）的积累在大多数老年人和患有脑淀粉样血管病的患者中很明显。在这里，我们利用人类多能干细胞从神经嵴祖细胞中生成血管平滑肌细胞（SMC），重现了Aβ代谢的脑脉管系统特异性特征。我们证实，脂蛋白受体LRP1在我们的神经嵴衍生的SMC中发挥作用，介导Aβ摄取和细胞内溶酶体降解。缺氧通过抑制LRP1表达显著损害SMC对Aβ清除的作用。这使我们能够开发一种使用神经嵴衍生的SMC并以缺氧作为应激模式的Aβ摄取检测方法。然后，我们以高通量形式测试了几种血管保护化合物，证明了基于干细胞的表型筛选对于新型治疗药物和药物再利用的价值，旨在减轻淀粉样蛋白负担。
