Given the remarkable diversity of the characteristics and functions of respiratory epithelial cells, the identification of lung progenitor cells, their differentiation, and the analysis of their regenerative capacities during lung formation and repair have been the focus of considerable research interest. Although the existence of multipotent progenitor cells capable of self-renewal and differentiation into distinct epithelial types has been demonstrated in the fetal lung (2
), the characterization of multipotent respiratory epithelial cell progenitors, or stem cells, that maintain lung homeostasis and mediate repair after injury in the mature lung is incomplete. The current view is that basal cells and secretory cells proliferate and differentiate into the distinct cell types of the conducting airways, whereas cuboidal type II AECs are the sole source of progenitor cells that proliferate and differentiate into squamous type I AECs during repair of the injured lung (9
Chapman et al. have identified a subpopulation of AECs expressing the laminin receptor, α6β4, that do not express proSP-C, a protein considered a cell-specific marker for mature type II AECs (5
). Purified α6β4-positive progenitor cells (which the authors refer to as β4+
cells) were found to proliferate and differentiate into both proSP-C–positive AECs and Clara cell secretory protein–positive (CCSP-positive) bronchiolar epithelial cells that contributed to highly organized bronchiolar and alveolar structures when implanted with fetal lung cells under the renal capsule of immunodeficient mice. Differentiated type II AECs expressing proSP-C did not have a similar proliferative capacity in vitro and did not contribute substantially to alveolar repair after severe bleomycin-induced injury. These α6β4-positive progenitor cells were found in both bronchiolar and alveolar regions of the normal mouse lung and lacked expression of proSP-C and the Clara cell marker CCSP, something that distinguishes them from the previously described dual proSP-C– and CCSP-positive bronchiolar-alveolar duct junction cells (12
The α6β4-positive cells accounted for approximately 8%–10% of AECs in the quiescent lung, and therefore represent a pool of multipotent progenitors that are likely to play an important role in the repair of the lung. Lineage-tracing studies presented by Chapman et al. demonstrated that the regeneration of new type II AECs seen after severe lung injury in the mouse depended on proliferation of α6β4-positive progenitors, rather than expansion of preexisting type II AECs (5
). It will be of considerable interest to determine the mechanisms by which α6β4-positive AECs self-renew and differentiate, whether they serve as sources of both type I and type II AECs, and whether they contribute to repair of conducting airways after clinically relevant injuries to the human lung. The identification and isolation of integrin α6β4–positive progenitor cells from human lung and from experimental models will be useful for identifying factors and conditions that optimize lung regeneration and repair.