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Gas exchange in the lung occurs within alveoli, air-filled sacs composed of type 2 and type 1 epithelial cells (AEC2s and AECls), capillaries, and various resident mesenchymal cells. Here, we use a combination of in vivo clonal lineage analysis, different injury/ repair systems, and in vitro culture of purified cell populations to obtain new information about the contribution of AEC2s to alveolar maintenance and repair. Genetic lineage-tracing experiments showed that surfactant protein C-positive (SFTPC-positive) AEC2s self renew and differentiate over about a year, consistent with the population containing long-term alveolar stem cells. Moreover, if many AEC2s were specifically ablated, high-resolution imaging of intact lungs showed that individual survivors undergo rapid clonal expansion and daughter cell dispersal. Individual lineage-labeled AEC2s placed into 3D culture gave rise to self-renewing "alveolospheres," which contained both AEC2s and cells expressing multiple AEC1 markers, including HOPX, a new marker for AECls. Growth and differentiation of the alveolospheres occurred most readily when cocultured with primary PDGFRα^sup +^ lung stromal cells. This population included lipofibroblasts that normally reside close to AEC2s and may therefore contribute to a stem cell niche in the murine lung. Results suggest that a similar dynamic exists between AEC2s and mesenchymal cells in the human lung.
Introduction
The lung is a complex organ wirh a large and highly vascularized epithelial surface area. Efficient gas exchange and host defense rely on the integrity of this epithelium and its dynamic interac- tion with surrounding mesenchyme. Lung cell turnover is nor- mally slow compared with other adult organs such as the skin and intestine. However, significant regeneration and repair are possible after physiologic insults, including pneumonectomy and severe respiratory infection (1-4). Understanding the regenerative capac- ity of the lung and the role of resident stem and progenitor cells is therefore of considerable practical and therapeutic interest.
Here, we focus on the maintenance and repair of the distal gas exchange region of the lung that is composed of millions of alveoli organized into hundreds of clusters or acini (5). Each alveolus con- tains cuboidal type 2 epithelial cells (AEC2s) expressing high levels of surfactant protein C (SFTPC) and very thin type 1 cells (AEC1 s) in close apposition to capillaries. Several pathologic conditions disrupt the delicate architecture of the alveoli - with...