Christine Cheung1,2,*, Yeek Teck Goh1, Jingxian Zhang1, Chenghan Wu3, Ernesto Guccione1,4
1 Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673
2 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, NUHS Tower Block, Singapore 119228
3 Faculty of Medicine, Nursing and Health Sciences, Monash University, 246 Clayton Road, Victoria 3168, Australia
4 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
Published in Cell Reports on 2nd October 2014.
There is a growing recognition of cerebrovascular contribution 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 on human pluripotent stem cells to generate vascular smooth muscle cells (SMCs) from neural crest progenitors, recapitulating brain vasculature-specific attributes in 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 ability of SMCs in Aβ clearance by suppressing LRP1 expression. This enables us to develop an assay of Aβ uptake 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, which aim at alleviating amyloid burden.
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