Advanced in vitro lung models for drug and toxicity screening: The promising role of induced pluripotent stem cells

The substantial socioeconomic burden of lung diseases, recently highlighted by the disastrous impact of the coronavirus disease 2019 (COVID-19) pandemic, accentuates the need for interventive treatments capable of decelerating disease progression, limiting organ damage, and contributing to a functional tissue recovery. However, this is hampered by the lack of accurate human lung research models, which currently fail to reproduce the human pulmonary architecture and biochemical environment. Induced pluripotent stem cells (iPSCs) and organ-on-chip (OOC) technologies possess suitable characteristics for the generation of physiologically relevant in vitro lung models, allowing for developmental studies, disease modeling, and toxicological screening. Importantly, these platforms represent potential alternatives for animal testing, according to the 3Rs (replace, reduce, refine) principle, and hold promise for the identification and approval of new chemicals under the European REACH (registration, evaluation, authorization and restriction of chemicals) framework. As such, this review aims to summarize recent progress made in human iPSC- and OOC-based in vitro lung models. A general overview of the present applications of in vitro lung models is presented, followed by a summary of currently used protocols to generate different lung cell types from iPSCs. Lastly, recently developed iPSC-based lung models are discussed.