Abstract
The neurovascular unit (NVU) is composed of neurons, astrocytes, pericytes, and endothelial cells that form the blood–brain barrier (BBB). The NVU regulates material exchange between the bloodstream and the brain parenchyma, and its dysfunction is a primary or secondary cause of many cerebrovascular and neurodegenerative disorders. As such, there are substantial research thrusts in academia and industry toward building NVU models that mimic endogenous organization and function, which could be used to better understand disease mechanisms and assess drug efficacy. Human pluripotent stem cells, which can self-renew indefinitely and differentiate to almost any cell type in the body, are attractive for these models because they can provide a limitless source of individual cells from the NVU. In addition, human-induced pluripotent stem cells (iPSCs) offer the opportunity to build NVU models with an explicit genetic background and in the context of disease susceptibility. Herein, we review how iPSCs are being used to model neurovascular and neurodegenerative diseases, with particular focus on contributions of the BBB, and discuss existing technologies and emerging opportunities to merge these iPSC progenies with biomaterials platforms to create complex NVU systems that recreate the in vivo microenvironment.
Highlights
The blood–brain barrier (BBB) maintains central nervous system (CNS) homeostasis by strictly regulating transport of ions, small molecules, proteins, and cells between the bloodstream and CNS (Obermeier et al, 2013)
We summarize these advancements in BBB modeling with induced pluripotent stem cells (iPSCs), discuss how iPSC-derived BBB endothelium could be used to enhance neurodegenerative disease mechanistic interrogations and drug screening campaigns, and outline engineering and fabrication approaches that may be used in future studies to produce neurovascular unit (NVU) models with more predictive power
In the animal models, BBB disruption precedes motor neuron death. Whether this vascular degeneration is a direct cause of the amyotrophic lateral sclerosis (ALS)-causing mutations or due to altered crosstalk with astrocytes or another NVU cell type remains to be determined, but the iPSC model represents a possible route for deconstructing these disease mechanisms and elucidating the role of BBB dysfunction in disease progression
Summary
The blood–brain barrier (BBB) maintains central nervous system (CNS) homeostasis by strictly regulating transport of ions, small molecules, proteins, and cells between the bloodstream and CNS (Obermeier et al, 2013). Immortalized BBB endothelial cell lines have been tested as an alternative to primary cells because they bypass the process of isolation from tissue and are derived from a clonal source (Weksler et al, 2005), but the immortalization process typically yields poor barrier functionality. These issues with primary cells and immortalized cell lines have led to the exploration of human-induced pluripotent stem cells (iPSCs) as a new cell source for modeling BBB. We summarize these advancements in BBB modeling with iPSCs, discuss how iPSC-derived BBB endothelium could be used to enhance neurodegenerative disease mechanistic interrogations and drug screening campaigns, and outline engineering and fabrication approaches that may be used in future studies to produce NVU models with more predictive power
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