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

Abstract

The lung's 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.

FGFR2b signalling restricts lineage-flexible alveolar progenitors during mouse lung development and converges in mature alveolar type 2 cells

“…In addition, this paper also found that loss of FGFR2 signalling in AT2 cells led to their transdifferentiation to AT1s, which supports what we have found during development. Another study looking at the role of FGFR2 signalling during late development (E16.5) similarly reports that FGFR2 was required to maintain AT2 cell fate and to prevent transdifferentiation to the AT1 lineage [ 30 ]. In this paper, the authors, like us, argue against the early lineage specification model, suggesting, instead, that early alveolar progenitors remain largely uncommitted up until E16.5.…”