The lung is a complex and highly specialized organ that carries out the vital task of gas exchange to deliver oxygen and concomitantly remove carbon dioxide from the organism´s circulation. In case of any epithelial damage, e.g. caused by inhalation of noxious agents or air-borne pollutants, it is of particular importance that injury is resolved promptly to restore the delicate pulmonary architecture.
In lungs, numerous regenerative cell types with differing lineage-potencies exist that may contribute to proper epithelial recovery. Among them, one of the most debated stem/progenitor cell candidates that raised ongoing scientific controversy is the rare subset of bronchioalveolar stem cells (BASCs). BASCs reside predominantly at bronchioalveolar duct junctions (BADJs) and characteristically co‐express mature bronchiolar and alveolar lineage markers, i.e. Club cell secretory protein (CCSP) and surfactant associated protein C (SPC). However, despite growing evidence that BASCs might act as an organ resident stem cell for the distal lung epithelium, this cell subset remained poorly characterized in vivo since all currently available mouse models lacked BASC‐specificity and additionally targeted either abundant Club cells (CCSP+) or alveolar type 2 cells (SPC+).
In a recent study, Max-Planck researchers therefore developed an innovative genetic targeting approach that allows selective genetic manipulation of cell types that can only be defined based on a specific dual-marker fingerprint. Their system relies on “split-effector molecules” that only reconstitute to a functional effector protein in marker co-expressing target cells. By applying BASC-specific mouse strains in different pulmonary disease models, the researchers were able to track BASCs and their derivatives throughout the regeneration process, uncovering substantial contribution of BASCs to epithelial renewal. Importantly, BASCs displayed multi-lineage differentiation potential and gave rise to both bronchiolar as well as alveolar descendants. Moreover, genetic ablation of BASCs compromised proper regeneration of distal airways. Taken together, their study defines BASCs as crucial components of the lung repair machinery and provides a paradigmatic example for the detection and manipulation of stem cells that cannot be recognized by a single marker alone.