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

• Published in: Nature communications Vol. 6; no. 1; p. 6727
• Main Authors: Jain, Rajan, Barkauskas, Christina E., Takeda, Norifumi, Bowie, Emily J., Aghajanian, Haig, Wang, Qiaohong, Padmanabhan, Arun, Manderfield, Lauren J., Gupta, Mudit, Li, Deqiang, Li, Li, Trivedi, Chinmay M., Hogan, Brigid L. M., Epstein, Jonathan A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-04-2015; Nature Publishing Group
• Subjects: 13/100; 14/1; 14/63; 631/136/532/489; 631/80/86; Animals; Biology; Cell Culture Techniques; Cell Differentiation; Cell Lineage - drug effects; Cell Lineage - physiology; Cell Proliferation; Cell self-renewal; Cell Tracking; Clone Cells; Crosses, Genetic; Drug dosages; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Experiments; Gene Expression; Genes, Reporter; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humanities and Social Sciences; Humans; Lungs; Male; Medicine; Mice; Mice, Transgenic; multidisciplinary; Organoids; Physiology; Plastic properties; Pneumonectomy; Proteins; Pulmonary Alveoli - cytology; Pulmonary Alveoli - drug effects; Pulmonary Alveoli - metabolism; Regeneration - physiology; Science; Science (multidisciplinary); Signal Transduction; Surfactants; Tamoxifen - pharmacology; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism
• ISSN: 2041-1723; 2041-1723
• 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.
Alveoli are the lung’s functional units composed of two major epithelial cell types, type I and type II. Type II cells are adult lung stem cells, but this study shows that differentiated Type I cells can also self-renew and give rise to Type II cells, revealing a bidirectional relationship between lung epithelial cell types.