The composition of the adult mouse lung epithelium during normal homeostasis. (A) The mouse lung is organized into three anatomical regions. The cartilaginous airways (trachea and main stem bronchi) are lined by a pseudostratified epithelium consisting of secretory (club and goblet), ciliated, basal and a few scattered neuroendocrine (NE) cells. Submucosal glands (SMGs) are located between cartilage rings of the proximal trachea and contain a stem cell population in their ducts (1). Label-retaining basal stem cells are often found in the intercartilage regions (2). The intralobar airway epithelium contains club, ciliated and clusters of NE cells called NE bodies (NEBs), which are often found at branching points. Naphthalene-resistant (variant) club cells are located adjacent to the NEBs (3) and at the bronchioalveolar duct junctions (BADJs) (4), and are presumed to be important for epithelial regeneration. The latter most likely represents a heterogeneous population containing bronchioalveolar stem cells (BASCs) and distal airway club stem cells (DASCs), which are activated after injury. The alveolar epithelium consists mainly of alveolar type (AT) I and ATII cells. The latter is a long-term self-renewing stem cell population also capable of giving rise to ATI cells. Lipofibroblasts in the lung interstitium express Fgf10 and are found juxtaposed to ATII stem cells (5). They are therefore an ideal candidate as a niche that controls the behavior of ATII cells during normal homeostasis and after injury. In addition, the alveoli harbor an alveolar progenitor cell enriched for α6β4 integrins. (B) Lineage relationships of lung epithelial stem cells and their progeny during normal homeostasis. The lung epithelium is maintained by three main stem cell populations: basal cells (cartilaginous airways), club cells (cartilaginous airways and bronchioles) and ATII cells (alveoli). Dashed arrows represent lineage relationships, which are likely to occur but have not yet been definitively established. For details see main text.