In vivo xenogenic reconstitution of human alveolar epithelial architecture and function

Abstract An urgent need exists for lung models that accurately replicate human physiological profiles. We developed a chimeric mouse model enabling targeted ablation of alveolar type 2 (AT2) cells and lung macrophages, creating niches for endoscopically transplanted human induced pluripotent stem cell (hiPSC)-derived lung progenitors (hLPs). These engrafted cells were retained for 24 weeks, demonstrating self-renewal and differentiation potential, surfactant protein secretion, and maintaining alveolar phosphate homeostasis, suggesting their maturation into AT2 cells. Furthermore, transplantation of hLPs derived from disease-specific hiPSCs recapitulated the phenotype of pulmonary alveolar microlithiasis. The architecture, function, and metabolism of human alveolar epithelium were accurately replicated in vivo. This model has the potential to link experimental models and first-in-human studies, facilitating the development of novel therapies for intractable lung diseases. Competing Interest Statement A.Y., S.G. and T.T are inventors of a patent application for lung-humanized mice. S.G. is an inventor of Kyoto University's patents for generating AOs. S.G. is a founder and a shareholder of HiLung, Inc. M.I. is a scientific adviser for xFOREST Therapeutics without a salary.