Induced lung epithelial-like cells derived by direct reprogramming rescue influenza virus-induced lung injury in mice.

We recently reported that a combination of four transcription factors (Nkx2-1, Foxa1, Foxa2, and Gata6) directly reprograms mouse embryonic fibroblasts (MEFs) into differentiated self-renewable alveolar epithelial-like cells in a serum-free 3D organoid system. Here, we aimed to generate induced pulmonary epithelial-like cells in serum-containing culture (iPULsSC) using the same four transcription factors in a serum-containing 3D culture system. We found that the global gene expression profile of iPULsSC was similar to that of alveolar epithelial type II (AT2) and alveolar type I (AT1) cells. Surfactant protein (SP)-C-positive iPULsSC displayed lamellar body-like structures, consistent with the features of AT2 cells. Furthermore, we provide evidence that intratracheal administration of iPULsSC rescued influenza virus-induced acute lung injury in mice. These findings suggest that iPULsSC can provide a potential source of lung epithelial cells for regenerative medicine. Reprogramming fibroblasts using serum-containing media, besides previously established serum-free systems, can provide a potential source of lung epithelial cells.