Modeling Cerebrovascular Pathophysiology in Amyloid-β Metabolism using Neural-Crest-Derived Smooth Muscle Cells

Abstract

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.

Intracerebral haemorrhage in Down syndrome: protected or predisposed?

“…The levels of LRP1 are reduced in patients with AD, and LRP1 levels also decline with age 48 . Recently, assays were developed to model these processes by using induced pluripotent stem cell models 49 . The effects of dup-APP and trisomy 21 on these processes are yet to be studied.…”

Gene Expression Profiling Supports the Neural Crest Origin of Adult Rodent Carotid Body Stem Cells and Identifies CD10 as a Marker for Mesectoderm-Committed Progenitors

“…To further distinguish the phenotype of NS cells from CD10 + and CD10− progenitors, we performed qPCRs with genes described in the literature as expressed in neural crest‐derived mesectodermal cells (green arrowheads in Fig. K) or in neural crest‐derived neural cells (red arrowheads in Fig. K) .…”

Modeling elastin-associated vasculopathy with patient induced pluripotent stem cells and tissue engineering

“…Differentiation protocols have been determined for VSMCs in particular, though as the iPSCs are pluripotent, these techniques can be and have been extrapolated to a variety of cell types [28]. Indeed, such protocols have been implemented to model SVAS, WBS, Marfan Syndrome, and Down Syndrome in two-dimensional culture systems effectively [11,29,30]. A two-dimensional system using iPSCs provides a unique and highly useful platform for a detailed mechanistic study of elastin-associated vasculopathy.…”

“…The iPSC platform, however, is highly suited to address the role or importance of lineage specificity on vascular pathology as pluripotent, patient-specific, progenitors can be directed to differentiate into VSMCs arising from varying lineage. Indeed, robust, detailed protocols have been developed for differentiating vast quantities of neural crest, lateral plate mesoderm, and paraxial mesoderm derived VSMCs for research purposes [29,30,76]. The iPSC model thus takes the advantages provided by an in vitro platform to investigate the role of lineage specificity on signal transduction, without the limitations of finite accessibility and expandability.…”