Type 2 Alveolar Cells Are Stem Cells in Adult Lung

J Clin Invest. 2013 Jul;123(7):3025-36. doi: 10.1172/JCI68782. Epub 2013 Jun 10.

Abstract

Gas exchange in the lung occurs within alveoli, air-filled sacs composed of type 2 and type 1 epithelial cells (AEC2s and AEC1s), 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 AEC1s. Growth and differentiation of the alveolospheres occurred most readily when cocultured with primary PDGFRα⁺ 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / physiology*
  • Alveolar Epithelial Cells / physiology*
  • Animals
  • Cell Differentiation
  • Cell Lineage
  • Cell Proliferation
  • Cells, Cultured
  • Coculture Techniques
  • Lung / pathology*
  • Lung Injury / chemically induced
  • Lung Injury / pathology
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Stem Cell Niche
  • Stromal Cells / metabolism

Substances

  • Receptor, Platelet-Derived Growth Factor alpha