Related Experiment Video
Updated: Sep 6, 2025
An In Vitro 3D Model and Computational Pipeline to Quantify the Vasculogenic Potential of iPSC-Derived Endothelial Progenitors
Published on: May 13, 2019
Brain microvascular endothelial cell dysfunction in an isogenic juvenile iPSC model of Huntington's disease
Raleigh M Linville1,2, Renée F Nerenberg1,2, Gabrielle Grifno1,2
1Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD, USA.
Insights
Huntington's disease (HD) CAG repeat expansion impairs brain microvascular endothelial-like cell (iBMEC) differentiation and function, contributing to blood-brain barrier (BBB) dysfunction. This research highlights BBB changes in HD progression.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Huntington's disease (HD) is an inherited neurodegenerative disorder linked to CAG repeat expansion in the huntingtin gene.
- Blood-brain barrier (BBB) dysfunction is increasingly implicated in HD progression, with studies noting microvascular changes and altered barrier function.
Purpose of the Study:
- To investigate the impact of CAG repeat expansion on the phenotype of brain microvascular endothelial-like cells (iBMECs) derived from induced pluripotent stem cells (iPSCs).
- To understand how CAG expansion affects BBB integrity and cellular responses in an in vitro model relevant to Huntington's disease.
Main Methods:
- Utilized an isogenic pair of iPSCs differentiated into iBMECs to model CAG repeat expansion effects.
- Assessed iBMEC differentiation, barrier function (transendothelial electrical resistance, permeability), protein expression, and transcriptional profiles.
- Examined iBMEC responses to pathological and therapeutic perturbations in a tissue-engineered BBB model.
Main Results:
- CAG expansion significantly altered iBMEC differentiation, reducing adherent endothelial cell percentage.
- HD iBMECs exhibited diminished transendothelial electrical resistance and reduced tight junction protein expression, but not increased paracellular permeability.
- Widespread transcriptional dysregulation was observed in HD iBMECs, alongside distinct cellular responses to stress and angiogenic factors.
Conclusions:
- CAG repeat expansion directly impacts brain microvascular endothelial cell phenotype and function, contributing to BBB dysfunction in Huntington's disease.
- The study provides cellular evidence supporting the role of BBB alterations in HD pathogenesis, independent of mutant huntingtin protein aggregation in these cells.
Abstract:
Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene, which leads to neuronal loss and decline in cognitive and motor function. Increasing evidence suggests that blood-brain barrier (BBB) dysfunction may contribute to progression of the disease. Studies in animal models, in vitro models, and post-mortem tissue find that disease progression is associated with increased microvascular density, altered cerebral blood flow, and loss of paracellular and transcellular barrier function. Here, we report on changes in BBB phenotype due to expansion of CAG repeats using an isogenic pair of induced pluripotent stem cells (iPSCs) differentiated into brain microvascular endothelial-like cells (iBMECs). We show that CAG expansion associated with juvenile HD alters the trajectory of iBMEC differentiation, producing cells with ~ two-fold lower percentage of adherent endothelial cells. CAG expansion is associated with diminished transendothelial electrical resistance and reduced tight junction protein expression, but no significant changes in paracellular permeability. While mutant huntingtin protein (mHTT) aggregates were not observed in HD iBMECs, widespread transcriptional dysregulation was observed in iBMECs compared to iPSCs. In addition, CAG expansion in iBMECs results in distinct responses to pathological and therapeutic perturbations including angiogenic factors, oxidative stress, and osmotic stress. In a tissue-engineered BBB model, iBMECs show subtle changes in phenotype, including differences in cell turnover and immune cell adhesion. Our results further support that CAG expansion in BMECs contributes to BBB dysfunction during HD.
More Related Videos
08:04Derivation, Expansion, Cryopreservation and Characterization of Brain Microvascular Endothelial Cells from Human Induced Pluripotent Stem Cells
Published on: November 19, 2020
07:40Generation of iPSC-derived Human Brain Organoids to Model Early Neurodevelopmental Disorders
Published on: April 14, 2017
Related Concept Videos
01:22iPS Cell Differentiation
01:21EPS and iPS Cells in Disease Research