Human pluripotent stem cells for the modelling and treatment of respiratory diseases

Abstract

Respiratory diseases are among the leading causes of morbidity and mortality worldwide, representing a major unmet medical need. New chemical entities rarely make it into the clinic to treat respiratory diseases, which is partially due to a lack of adequate predictive disease models and the limited availability of human lung tissues to model respiratory disease. Human pluripotent stem cells (hPSCs) may help fill this gap by serving as a scalable human in vitro model. In addition, human in vitro models of rare genetic mutations can be generated using hPSCs. hPSC-derived epithelial cells and organoids have already shown great potential for the understanding of disease mechanisms, for finding new potential targets by using high-throughput screening platforms, and for personalised treatments. These potentials can also be applied to other hPSC-derived lung cell types in the future. In this review, we will discuss how hPSCs have brought, and may continue to bring, major changes to the field of respiratory diseases by understanding the molecular mechanisms of the pathology and by finding efficient therapeutics.

A lentiviral toolkit to monitor airway epithelial cell differentiation using bioluminescence

“…The non-destructive nature of the luciferase assay on live cell cultures enables repeated measurements to be made from the same cultures over a time course, with these cultures then available for additional end-point assays (such as TEER readings, ciliary beat frequency analyses, qPCR and immunofluorescence). Further, the lentiviral constructs reported here could be useful tools in iPSC-derived airway epithelial cell differentiation protocols to provide real-time monitoring of cell type emergence and/or to act as a quality control measure between cultures (40, 41). Given the existence of multiple luciferases that luminesce at different wavelengths (42), in the future it may be possible to generate a lentiviral vector that monitors multiple airway epithelial cell populations simultaneously.…”

Differentiation and on axon-guidance chip culture of human pluripotent stem cell-derived peripheral cholinergic neurons for airway neurobiology studies

“…To implement patient-specific neuro-effector cultures, one could also differentiate smooth muscle cells from hPSCs. However, among the many differentiation protocols that are available for smooth muscle cells, none is able to generate tissue-specific smooth muscle cells ( Goldsteen et al, 2021 ). We valued the inherent properties that ASM cells have to aid the differentiation into airway neurons specifically, hence our choice for immortalized human ASM cells.…”

Investigating pulmonary neuroendocrine cells in human respiratory diseases with airway models

“…hPSCs – either embryonic stem cells or hiPSCs – provide an unlimited source of cells that can be differentiated into lung progenitor cells. The ability to generate airway epithelia from hPSCs has provided an effective approach to study lung development, model respiratory diseases and conduct drug screening ( Goldsteen et al, 2021 ). Several differentiation protocols to derive airway epithelial cells from hPSCs in two-dimensional (2D) cultures ( Firth et al, 2014 ; Huang et al, 2014 ; Mou et al, 2012 ; Wong et al, 2012 ) and in three-dimensional (3D) organoids ( Chen et al, 2017 ; Dye et al, 2015 ; Gotoh et al, 2014 ; Konishi et al, 2016 ; McCauley et al, 2017 ) have been established that aim to recapitulate lung development in vitro through the precise activation and/or inhibition of key signalling pathways in a carefully timed manner.…”