CBE Seminar: “Engineering Technologies for Enhanced Modeling, Detection, and Treatment of Neurological Disease” (Alice Stanton, MIT)

Abstract:

Neurological conditions are the leading cause of illness worldwide, though over 92% of clinically tested CNS drug candidates fail to become treatments. Contributing to this high failure rate is a lack of understanding of human disease mechanisms, technologies to address them, and the restrictive blood-brain barrier (BBB), which most compounds fail to cross. New models are critically needed that more faithfully recapitulate human neurological disease, providing a tool for enhanced discovery of biomarkers and targets, effective therapeutic development, and personalized drug screening. In this seminar, I will present my work in (1) developing biomaterials-based platforms to mimic physiological conditions, probe fundamental questions, and utilize as cell-carrying scaffolds, (2) establishing a multicellular human cell-based model of the brain, miBrain, that incorporates neuronal, glial, vascular, and immune components into 3D brain tissue with structural organization, combining the power of induced pluripotent stem cell (iPSC) technology and tissue engineering, and (3) utilizing the multicellular brain model to interrogate disease pathogenesis and delivery across the BBB, harnessing a microfluidic platform I developed to enable 3D vascular perfusion within the miBrain. In my doctoral work, I developed biomaterials-based platforms to probe fundamental questions of stem cell mechanotransduction and to utilize as cell-carrying scaffolds in tissue engineering approaches. In my postdoctoral work, I applied these engineering tools to develop an advanced preclinical brain model, extensively characterized and validated the platform, and leveraged this system to model disease and BBB transport. I differentiate iPSCs into each of the six major brain cell types and assemble them in the Neuromatrix Hydrogel I developed to incorporate brain-niche cues and support cell network co-formation, and culture them in high throughput well format or perfusable chip format. miBrains form integrated 3D immune-glial-neurovascular units with enhanced cell- and tissue-scale phenotypes inclusive of myelinated neuronal networks, microglial immune cells, and BBB. To enable perfusable vasculature within the miBrain, I developed a novel microfluidic platform, the GelChip, via a 3D printing fabrication strategy, that supports 3D network formation within complex co-cultures and engineered hydrogels to form the miBrain-on-Chip. Harnessing iPSCs from patient lines and genome editing to isolate the functional consequences of specific mutations, I can form multicellular brain models across patient cohorts, assess disease susceptibility, probe mechanisms, and screen putative interventions. I have harnessed the miBrain to model APOE4 risk for Alzheimer’s Disease, recapitulating canonical disease hallmarks of increased reactive astrocytes, amyloid aggregates, and neuronal tau phosphorylation. Further, I found that APOE4 astrocytes are sufficient to increase neuronal tau phosphorylation via crosstalk with microglia. I have thus established a novel preclinical brain model with broad utility for dissecting disease mechanisms, assessing delivery to the brain, and probing barrier function and other hallmarks in contexts of disease. In the conclusion of this seminar, I will explore how multicellular human cell-based brain models and their underlying technologies and approaches can be leveraged to accelerate mechanistic understanding, therapeutic target identification, and drug candidate optimization for treatment delivery and efficacy.