Current strategies and opportunities to manufacture cells for modeling human lungs

Chronic lung diseases remain major healthcare burdens, for which the only curative treatment is lung transplantation. In vitro human models are promising platforms for identifying and testing novel compounds to potentially decrease this burden. Directed differentiation of pluripotent stem cells is an important strategy to generate lung cells to create such models. Current lung directed differentiation protocols are limited as they do not 1) recapitulate the diversity of respiratory epithelium, 2) generate consistent or sufficient cell numbers for drug discovery platforms, and 3) establish the histologic tissue-level organization critical for modeling lung function. In this review, we describe how lung development has formed the basis for directed differentiation protocols, and discuss the utility of available protocols for lung epithelial cell generation and drug development. We further highlight tissue engineering strategies for manipulating biophysical signals during directed differentiation such that future protocols can recapitulate both chemical and physical cues present during lung development.