![]() In AT2 lin closeup, Fgfr2 (red) remains on in developing AT2 cells (arrowhead) but downregulated in neighboring developing AT1 cells, and although BP/AT1 marker (Pdpn) is still detected it too will soon be downregulated as developing AT2 cell matures (see Supplementary Fig. 1a). ![]() Note in BP close-up BPs are cuboidal, Pdpn-expressing cells. Boxed regions, close-ups, and split channels at the right of the bipotent progenitor (BP) and developing AT2 lineage cell (AT2 lin). c e17.5 lung immunostained for Fgfr2 (red), bipotent progenitor (BP) and AT1 marker podoplanin (Pdpn, green), and epithelial marker E-cadherin (E-cad, white). b Expression of Fgfr2b ligand genes in distal (alveolar) endothelium and mesenchyme from scRNAseq of e18.5 lung. (Note due to the very high expression of Sftpc in bipotent progenitors, there is a temporal lag in the extinction of the transcripts in newly-differentiating AT1 cells and thus some nascent AT1 cells co-express Sftpc and Rage.) Ubiq, ubiquitously-expressed control genes. 11 by expression of alveolar lineage markers like the four shown (“Lineage”) including two that restrict from BP to AT2 lineage (BP/AT2, Sftpc) or to AT1 lineage (BP/AT1, Rage). Cells (columns) are arranged in developmental pseudotime (BP, bipotent progenitors, center AT1 lineage to the left AT2 lineage to the right) determined as described in ref. We propose that Fgfr2 signaling selects AT2 fate during development, induces a cell non-autonomous AT1 differentiation signal, then continuously maintains AT2 identity and survival throughout life.Įxpression of Fgfr2 and its ligands during alveolar differentiationĪ Expression of Fgfr2 and the four other receptor genes most selectively expressed in alveolar type 2 (AT2) cell lineage (“Receptors”) from single-cell RNA sequencing (scRNAseq) analysis of distal (alveolar) epithelial cells from embryonic day 18.5 (e18.5) mouse lung. Fgfr2 loss in AT2 cells perinatally results in reprogramming to AT1 identity, whereas loss or inhibition later in life triggers AT2 apoptosis and compensatory regeneration. FGF signaling directly and cell autonomously specifies AT2 fate progenitors lacking Fgfr2 in vitro and in vivo exclusively acquire AT1 fate. Its ligands are expressed in surrounding mesenchyme and can, in the absence of exogenous mechanical cues, induce progenitors to form alveolospheres with intermingled AT2 and AT1 cells. Fgfr2 is expressed in the developing progenitors in mouse then restricts to nascent AT2 cells and remains on throughout life. Here we show the critical determinant is FGF signaling. They arise from a bipotent progenitor whose differentiation is thought to be dictated by differential mechanical forces. The lung’s gas exchange surface is comprised of alveolar AT1 and AT2 cells that are corrupted in several common and deadly diseases.
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