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

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

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Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute of Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke Medicine, Durham, North Carolina 27710, USA.
Department of Cell Biology, Duke Medicine, Durham, North Carolina 27710, USA.


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.

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