Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung

Nat Commun. 2015 Apr 13;6:6727. doi: 10.1038/ncomms7727.


The plasticity of differentiated cells in adult tissues undergoing repair is an area of intense research. Pulmonary alveolar type II cells produce surfactant and function as progenitors in the adult, demonstrating both self-renewal and differentiation into gas exchanging type I cells. In vivo, type I cells are thought to be terminally differentiated and their ability to give rise to alternate lineages has not been reported. Here we show that Hopx becomes restricted to type I cells during development. However, unexpectedly, lineage-labelled Hopx(+) cells both proliferate and generate type II cells during adult alveolar regrowth following partial pneumonectomy. In clonal 3D culture, single Hopx(+) type I cells generate organoids composed of type I and type II cells, a process modulated by TGFβ signalling. These findings demonstrate unanticipated plasticity of type I cells and a bidirectional lineage relationship between distinct differentiated alveolar epithelial cell types in vivo and in single-cell culture.

Publication types

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

MeSH terms

  • Animals
  • Cell Culture Techniques
  • Cell Differentiation
  • Cell Lineage / drug effects
  • Cell Lineage / physiology*
  • Cell Proliferation
  • Cell Tracking
  • Clone Cells
  • Crosses, Genetic
  • Epithelial Cells / cytology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gene Expression
  • Genes, Reporter
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Pneumonectomy
  • Pulmonary Alveoli / cytology*
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / metabolism
  • Regeneration / physiology*
  • Signal Transduction
  • Tamoxifen / pharmacology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism


  • Hod protein, mouse
  • Homeodomain Proteins
  • Transforming Growth Factor beta
  • Tamoxifen
  • Green Fluorescent Proteins