Isogenic induced-pluripotent-stem-cell-derived airway- and alveolus-on-chip models reveal specific innate immune responses.

The development of microphysiological systems for preclinical research is often hindered by the limited availability of reliable cell sources, especially when multiple organs or tissues from a single patient are needed for comparative studies of the host innate immune response. In this study, we develop human airway-on-chip and alveolus-on-chip models using lung progenitor cells derived from isogenic induced pluripotent stem cells. Our results using SARS-CoV-2 and influenza reveal distinct initial innate immune responses in the airway- and alveolus-on-chip models. SARS-CoV-2-infected airway chips show a robust early interferon-dependent innate immune response, while alveolus chips show dysregulated and delayed interferon activation alongside a significantly upregulated chemokine pathway. In contrast, influenza infection induces a more pronounced innate immune response and greater cellular damage in both chips compared with SARS-CoV-2. Consequently, airway- and alveolus-on-chip models derived from induced pluripotent stem cells offer a viral pathology platform with screening potential for future therapeutic agents.