Endowing Flexibility of Alveolar Type II Cells to Recapitulate Development From Lung Bud to Alveoli

Abstract

ABSTRACT Alveolar type 2 (AT2) cells, which originate from bud tip progenitors during lung development, maintain pulmonary homeostasis through surfactant secretion and regenerative capacity, yet their plasticity has been challenging to model in vitro, limiting their applications in disease modeling and regenerative therapy. Here, a chemically defined reprogramming strategy is developed that enables efficient conversion of adult human AT2 cells into a highly expandable alveolar progenitor‐like state that, at late passages, closely resembles primitive lung bud tip epithelium. These progenitor cells robustly self‐organize into three‐dimensional alveolar progenitor‐like organoids (APLOs), which can be further efficiently differentiated into mature alveolar‐like organoids (ALOs). In vitro, ALOs serve as a physiologically relevant platform for modeling influenza A virus (IAV) infection and mounting innate immune responses characterized by interferon signaling, thereby enabling mechanistic studies of viral pathogenesis and host defense. In vivo, following intratracheal transplantation into lung‐injured mice, APLO‐derived cells exhibit stable engraftment and differentiate into alveolar epithelial lineages, leading to improvement in pulmonary function. In summary, this study establishes an adult‐derived, expandable alveolar progenitor platform generated through chemical reprogramming that recapitulates key aspects of alveolar development, disease modeling, and regenerative potential.