Stem cell populations contributing to regeneration of the proximal airway epithelium. (A) Widely used tracheal injury models such as the SO2, the naphthalene (Npt), and the tracheal transplant models, are used to study the contribution of stem cell populations to epithelial regeneration. SO2 and naphthalene injury destroy most luminal cells (1). Although surviving club cells can contribute to epithelial regeneration in the trachea following injury, the majority of newly generated club and ciliated cells arise from activated basal stem cells. A basal cell-like stem cell population residing in submucosal gland (SMG) ducts can also contribute to the regenerative process under these conditions, although they are probably employed to a larger extent after more severe injury. Although basal stem cells are presumed to be at the apex of stem cell hierarchy, club cells have been shown to be able to dedifferentiate and give rise to basal cells after diphtheria toxin-mediated depletion of the basal cell population (2). Club cell-derived basal cells can then give rise to club and ciliated cells during normal homeostasis. A more drastic epithelial injury caused by the loss of blood supply is obtained by the tracheal transplant model, which destroys nearly all epithelial cells except for a few injury resistant basal cells and SMG duct stem cells (3). After blood supply is reestablished, these surviving stem cells can then restore the tracheal surface and SMG epithelium. Colored cell outlines represent lineage trace markers. (B) Lineage relationships of lung epithelial stem cells and their differentiated progeny during regeneration of the tracheal epithelium after SO2/naphthalene injury (left), diphtheria toxin-mediated basal cell depletion (middle) and hypoxic ischemic injury using the tracheal transplant model (right). Dashed arrows represent lineage relationships, which are likely to occur but have not yet been definitively established. For details see main text.