Induced pluripotent stem cell-based organ-on-a-chip as personalized drug screening tools: A focus on neurodegenerative disorders

Abstract

The Organ-on-a-Chip (OoC) technology shows great potential to revolutionize the drugs development pipeline by mimicking the physiological environment and functions of human organs. The translational value of OoC is further enhanced when combined with patient-specific induced pluripotent stem cells (iPSCs) to develop more realistic disease models, paving the way for the development of a new generation of patient-on-a-chip devices. iPSCs differentiation capacity leads to invaluable improvements in personalized medicine. Moreover, the connection of single-OoC into multi-OoC or body-on-a-chip allows to investigate drug pharmacodynamic and pharmacokinetics through the study of multi-organs cross-talks. The need of a breakthrough thanks to this technology is particularly relevant within the field of neurodegenerative diseases, where the number of patients is increasing and the successful rate in drug discovery is worryingly low. In this review we discuss current iPSC-based OoC as drug screening models and their implication in development of new therapies for neurodegenerative disorders.

Keywords: Induced pluripotent stem cells; drug screening; neurodegenerative disorders; organ-on-a-chip.

Figure 1.

Graphic representation of the cell culture models hosted in the organs-on-a-chip involved in ADME. The scheme highlights the main cell types that should be included into the most advanced state-of-the art microfluidic devices for drug screening. The solid arrows point out the direction of diffusion of drug and/or its metabolite. The dashed arrows indicate the fate of orally administered drug in the human body. Created with BioRender.com.

Figure 2.

Example of different organ-on-a-chip (OoC) design for the Blood-Brain-Barrier (BBB) and the brain: (a) a pumpless 2D microfluidic device mimicking the BBB and hosting a coculture of iBMECs and rat primary astrocytes, (b) a 3D BBB-on-a-chip, with iPSC-derived ECs and human primary astrocytes and pericytes embedded in a fibrin hydrogel in a microfluidic system, (c) a 2D microfluidic device hosting iPSC-derived dopaminergic, glutamatergic and GABAergic neurons in different chambers connected by microgrooves enabling connectivity studies, (d) NVU-on-a-chip microfluidic device with the BBB constituted by primary human BMVECs, astrocytes, and pericytes and the brain by iPSC-derived neurons and astrocytes embedded in a 3D collagen gel, and (e) a schematic example of an iPSC-derived brain organoid developed in a microfluidic device, embedded in a 3D Matrigel matrix. Created with BioRender.com. Source: Adapted with permission from Wang et al. in Biotechnol. Bioeng., Lee et al. in Adv. Healthc. Mater., Fantuzzo et al. in Technology, Brown et al. in J. Neuroinflammation, Wang et al. in Lab Chip. iBMECs: induced brain endothelial cells; BBB: blood-brain-barrier; iPSCs: induced pluripotent stem cells; ECs: endothelial cells; GABA: gamma-Aminobutyric acid; NVU: neurovascular unit; BMVEC: brain microvasculature endothelial cells.

Figure 3.

Examples of neurodegenerative disease-on-a-chip: (a) a fully iPSC-derived NVU-on-a-chip, iPSCs were obtained from HD patients or healthy subjects to study BBB permeability to different drugs: FITC-dextran, fluorescent glucose analog 2-NBDG, retigabine, levetiracetam, and colchicine, (b) Xona Microfluidics devices were seeded with iPSC-derived neurons in the somal compartment; once the axons grew into the microgrooves and reached the axonal compartment, labeled Tau monomers or oligomers were added to the somal compartment to study cellular uptake and axonal transport, (c) the human nigrostriatal pathway on-a-chip, midbrain dopaminergic neurons (DANs), and striatal medium spiny neurons (MSNs) were derived from PD patients carrying OPA1 mutation iPSCs to study mitochondrial and synaptic impairment, (d) a microfluidic device used to study the protective and anti-aggregation properties of the molecular tweezer CLR01 on α-synuclein uptake and transport by iPSC-derived dopaminergic neurons. Created with BioRender.com. Source: Adapted with permission from Vatine et al. in Cell Stem Cell., Usenovic et al. in J. Neurosci., Iannelli et al. in Cell Rep., Bengoa-Vergniory et al. in Nat. Commun. iPSCs: induced pluripotent stem cells; NVU: neurovascular unit; HD: Huntington’s disease; BBB: blood-brain-barrier; FITC: Fluorescein isothiocyanate.