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

TLDR

Adult lung alveoli comprise type I and type II epithelial cells, with type II cells serving as progenitors while type I cells are traditionally viewed as terminally differentiated, making the plasticity of these differentiated cells a central research focus. Using lineage tracing and clonal 3D culture, the study demonstrates that Hopx+ type I cells can proliferate and generate type II cells, a process regulated by TGFβ signaling. The findings reveal that differentiated type I cells possess unanticipated plasticity, self‑renew, and can produce type II cells, establishing a bidirectional lineage relationship between the two alveolar epithelial cell types.

Abstract

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.