Brownfield, D. G. | bioRxiv Science

bioRxiv2022

Alveolar cell fate selection and lifelong maintenance of AT2 cells by FGF signaling

The lungs gas exchange surface comprises thin alveolar type 1 (AT1) cells and cuboidal surfactant-secreting AT2 cells that are corrupted in some of the most common and deadly diseases including adenocarcinoma, emphysema, and SARS/Covid-19. These cells arise from an embryonic progenitor whose development into an AT1 or AT2 cell is thought to be dictated by differential mechanical forces. Here we show the critical determinant is FGF signaling. FGF Receptor 2 (Fgfr2) is expressed in mouse progenitors then restricts to nascent AT2 cells and remains on throughout life. Its ligands are expressed in surrounding mesenchyme and can, in the absence of differential mechanical cues, induce purified, uncommitted E16.5 progenitors to form alveolus-like structures with intermingled AT2 and AT1 cells. FGF signaling directly and cell autonomously specifies AT2 fate; progenitors lacking Fgfr2 in vitro and in vivo exclusively acquire AT1 fate. Fgfr2 loss in AT2 cells perinatally results in reprogramming to AT1 fate, whereas loss or inhibition later in life immediately triggers AT2 apoptosis followed by a compensatory regenerative response. We propose Fgfr2 signaling directly selects AT2 fate during development, induces a cell non-autonomous secondary signal for AT1 fate, and stays on throughout life to continuously maintain healthy AT2 cells. One Sentence SummaryFGF signaling induces and distinguishes the two cell types of the lungs gas exchange surface, and the pathway remains on throughout life to maintain one that can be transformed into lung cancer or targeted in the deadly form of SARS/Covid-19.

developmental biology↗

bioRxiv2021

Alveoli form directly by budding led by a single epithelial cell

Oxygen passes along the ramifying branches of the lungs bronchial tree and enters the blood through millions of tiny, thin-walled gas exchange sacs called alveoli. Classical histological studies have suggested that alveoli arise late in development by a septation process that subdivides large air sacs into smaller compartments. Although a critical role has been proposed for contractile myofibroblasts, the mechanism of alveolar patterning and morphogenesis is not well understood. Here we present the three-dimensional cellular structure of alveoli, and show using single-cell labeling and deep imaging that an alveolus in the mouse lung is composed of just 2 epithelial cells and a total of a dozen cells of 7 different types, each with a remarkable, distinctive structure. By mapping alveolar development at cellular resolution at a specific position in the branch lineage, we find that alveoli form surprisingly early by direct budding of epithelial cells out from the airway stalk between enwrapping smooth muscle cells that rearrange into a ring of 3-5 myofibroblasts at the alveolar base. These alveolar entrance myofibroblasts are anatomically and developmentally distinct from myofibroblasts that form the thin fiber partitions of alveolar complexes ( partitioning myofibroblasts). The nascent alveolar bud is led by a single alveolar type 2 (AT2) cell following selection from epithelial progenitors; a lateral inhibitory signal transduced by Notch ensures selection of only one cell so its trailing neighbor acquires AT1 fate and flattens into the cup-shaped wall of the alveolus. Our analysis suggests an elegant new model of alveolar patterning and formation that provides the foundation for understanding the cellular and molecular basis of alveolar diseases and regeneration. One Sentence SummaryWe report a direct budding mechanism of alveolar development distinct from the classical model of subdivision ( septation) of large air sacs.

developmental biology↗