Isogenic iPSC-derived proximal and distal lung-on-chip models reveal tissue and virus-specific immune responses in human lungs [Alveoli Bottom]

MPS (Micro-physiological systems) are foreseen to play a crucial role in preclinical studies, particularly for future viral pandemics. However, the development of an MPS is often hindered by the shortage of reliable cell sources, especially different organs/tissues from a single patient to compare the host immune response. Here, we developed a human airway-on-chip and an alveolus-on-chip model using induced pluripotent stem cell (iPSC)-derived isogenic lung progenitor cells. Both chips showed replication of two different respiratory viruses, SARS-CoV-2 and Influenza virus, related cellular damage, and innate immune response on-chip. We report differential immune response against SARS-CoV-2 between the proximal and distal lung on-chip models. Airway chips elicit a robust IFN-dependent immune response whereas alveolus chips exhibit a dysregulated IFN activation but a significantly upregulated chemokine pathway. On the other hand, Influenza virus infection elicits an immune response and cellular damage of higher magnitude in both chips in comparison to SARS-CoV-2. The results show potential of the iPSC-derived lung-on-chip models to rapidly understand viral pathology and screening drugs for future pandemics.