Neurological disorders are the leading cause of disability and the second largest cause of death worldwide. Despite significant research efforts, neurology remains one of the most failure-prone areas of drug development. The complexity of the human brain, boundaries to examining the brain directly in vivo, and the significant evolutionary gap between animal models and humans, all serve to hamper translational success. Recent advances in microfluidic in vitro models have provided new opportunities to study human cells with enhanced physiological relevance. The ability to precisely micro-engineer cell-scale architecture, tailoring form and function, has allowed for detailed dissection of cell biology using microphysiological systems (MPS) of varying complexities from single cell systems to "Organ-on-chip" models. Simplified neuronal networks have allowed for unique insights into neuronal transport and neurogenesis, while more complex 3D heterotypic cellular models such as neurovascular unit mimetics and "Organ-on-chip" systems have enabled new understanding of metabolic coupling and blood-brain barrier transport. These systems are now being developed beyond MPS toward disease specific micro-pathophysiological systems, moving from "Organ-on-chip" to "Disease-on-chip." This review gives an outline of current state of the art in microfluidic technologies for neurological disease research, discussing the challenges and limitations while highlighting the benefits and potential of integrating technologies. We provide examples of where such toolsets have enabled novel insights and how these technologies may empower future investigation into neurological diseases.

Advances in microfluidic in vitro systems for neurological disease modeling

The induced pluripotent stem cell (iPSC) technology has transformed in vitro research and holds great promise to advance regenerative medicine. iPSCs have the capacity for an almost unlimited expansion, are amenable to genetic engineering, and can be differentiated into most somatic cell types. iPSCs have been widely applied to model human development and diseases, perform drug screening, and develop cell therapies. In this review, we outline key developments in the iPSC field and highlight the immense versatility of the iPSC technology for in vitro modeling and therapeutic applications. We begin by discussing the pivotal discoveries that revealed the potential of a somatic cell nucleus for reprogramming and led to successful generation of iPSCs. We consider the molecular mechanisms and dynamics of somatic cell reprogramming as well as the numerous methods available to induce pluripotency. Subsequently, we discuss various iPSC-based cellular models, from mono-cultures of a single cell type to complex three-dimensional organoids, and how these models can be applied to elucidate the mechanisms of human development and diseases. We use examples of neurological disorders, coronavirus disease 2019 (COVID-19), and cancer to highlight the diversity of disease-specific phenotypes that can be modeled using iPSC-derived cells. We also consider how iPSC-derived cellular models can be used in high-throughput drug screening and drug toxicity studies. Finally, we discuss the process of developing autologous and allogeneic iPSC-based cell therapies and their potential to alleviate human diseases. 

Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications

The blood–brain barrier (BBB) regulates the delivery of oxygen and important nutrients to the brain through active and passive transport and prevents neurotoxins from entering the brain. It also has a clearance function and removes carbon dioxide and toxic metabolites from the central nervous system (CNS). Several drugs are unable to cross the BBB and enter the CNS, adding complexity to drug screens targeting brain disorders. A well-functioning BBB is essential for maintaining healthy brain tissue, and a malfunction of the BBB, linked to its permeability, results in toxins and immune cells entering the CNS. This impairment is associated with a variety of neurological diseases, including Alzheimer’s disease and Parkinson’s disease. Here, we summarize current knowledge about the BBB in neurodegenerative diseases. Furthermore, we focus on recent progress of using human-induced pluripotent stem cell (iPSC)-derived models to study the BBB. We review the potential of novel stem cell-based platforms in modeling the BBB and address advances and key challenges of using stem cell technology in modeling the human BBB. Finally, we highlight future directions in this area.

Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

Cell models for Alzheimer's and Parkinson's disease: At the interface of biology and drug discovery.

The neurovascular unit (NVU), consisting of neurons, glial cells, vascular cells (endothelial cells, pericytes and vascular smooth muscle cells (VSMCs)) together with the surrounding extracellular matrix (ECM), is an important interface between the peripheral blood and the brain parenchyma. Disruption of the NVU impacts on blood-brain barrier (BBB) regulation and underlies the development and pathology of multiple neurological disorders, including stroke and Alzheimer's disease (AD). The ability to differentiate induced pluripotent stem cells (iPSCs) into the different cell types of the NVU and incorporate them into physical models provides a reverse engineering approach to generate human NVU models to study BBB function. To recapitulate the in vivo situation such NVU models must also incorporate the ECM to provide a 3D environment with appropriate mechanical and biochemical cues for the cells of the NVU. In this review, we provide an overview of the cells of the NVU and the surrounding ECM, before discussing the characteristics (stiffness, functionality and porosity) required of hydrogels to mimic the ECM when incorporated into in vitro NVU models. We summarise the approaches available to measure BBB functionality and present the techniques in use to develop robust and translatable models of the NVU, including transwell models, hydrogel models, 3D-bioprinting, microfluidic models and organoids. The incorporation of iPSCs either without or with disease-specific genetic mutations into these NVU models provides a platform in which to study normal and disease mechanisms, test BBB permeability to drugs, screen for new therapeutic targets and drugs or to design cell-based therapies.

3D hydrogel models of the neurovascular unit to investigate blood-brain barrier dysfunction

Towards Advanced iPSC-based Drug Development for Neurodegenerative Disease.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with a lifetime risk of 1:400, primarily affecting upper and lower motor neurons. Unfortunately, there are only two drugs approved to treat ALS, which increase patient survival only by a few months. This highlights the urgent need for developments of new ALS modifying therapies, which have been hampered by high failure rate of new drug candidates during clinical trials. Stem cell therapy is one of the promising approaches that is in development for treating ALS. The beneficial effects of stem cell therapy rely on their paracrine signaling, suggesting extracellular vesicles (EVs) as possible non-cell based therapy. In particular, mesenchymal stem cells (MSCs) contribute to reparative process. To better translate and assess therapeutic potential of MSC-EVs, we combined state of the art induced pluripotent stem cell (iPSC) technologies to obtain patient-derived spinal low motor neurons and a comprehensive proteomic analysis to decipher the proteomic signature. To investigate the key molecular perturbations underlying disease pathology of ALS, a comprehensive proteomic analysis was performed showing mutation-specific and common ALS-specific changes. Mutation-specific effects in ALS motor neurons with hexanucleotide expansion in C9ORF72 exhibit dysregulation in proteins targeting to ER and cytoplasmic translation. In FUS-ALS motor neurons, iron ion homeostasis and cellular response to stress processes are affected. In ALS-TDP-43 motor neurons protein transport and localization are affected. Common ALS mechanisms such as mRNA splicing, proteasomal ubiquitin and mitochondrial associated processes are dysregulated. Furthermore, we demonstrated these underlying dysregulated mechanisms after treatment with MSC-EVs. More importantly, MSC-EV treatment can restore the protein expression levels impaired in ALS suggesting for future therapeutic potential for ALS.

Amyotrophic Lateral Sclerosis Proteomic Signature And Treatment With Mesenchymal Stem Cell-derived Extracellular Vesicles

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Towards Advanced iPSC-based Drug Development for Neurodegenerative Disease.

Amyotrophic Lateral Sclerosis Proteomic Signature And Treatment With Mesenchymal Stem Cell-derived Extracellular Vesicles