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

Abstract

The specification, characterization, and fate of alveolar type 1 and type 2 (AT1 and AT2) progenitors during embryonic lung development are poorly defined. Current models of distal epithelial lineage formation fail to capture the heterogeneity and dynamic contribution of progenitor pools present during early development. Furthermore, few studies explore the pathways involved in alveolar progenitor specification and fate. In this paper, we build upon our previously published work on the regulation of airway epithelial progenitors by fibroblast growth factor receptor 2b (FGFR2b) signalling during early (E12.5) and mid (E14.5) pseudoglandular stage lung development. Our results suggest that a significant proportion of AT2 and AT1 progenitors are lineage-flexible during late pseudoglandular stage development, and that lineage commitment is regulated in part by FGFR2b signalling. We have characterized a set of direct FGFR2b targets at E16.5 which are likely involved in alveolar lineage formation. These signature genes converge on a subpopulation of AT2 cells later in development and are downregulated in AT2 cells transitioning to the AT1 lineage during repair after injury in adults. Our findings highlight the extensive heterogeneity of pneumocytes by elucidating the role of FGFR2b signalling in these cells during early airway epithelial lineage formation, as well as during repair after injury.

PRDM3/16 Regulate Chromatin Accessibility Required for NKX2-1 Mediated Alveolar Epithelial Differentiation and Function

“…Consistent with the scRNA and immunofluorescence data, genes associated with surfactant biosynthesis ( Sftpb, Sftpc , and Sftpd) , genes associated with surfactant homeostasis ( Ctsh ) and those associated with lipid metabolism ( Lpcat1, Abca3, Fasn, Scd1) were significantly decreased in bulk epithelial RNA (Figure 3B, C). Several genes not found to be differentially expressed in the single cell data but known to be required for normal lung development and AT2 cell maturation were differentially expressed in the bulk RNA analysis including Fgfr2 (−1.73), 47,48 Cebpa (−1.83), 49 Etv5 (−2.82), 50,51 and Wnt5a (2.1) 52 (Figure 3A). RNAs associated with the main AT1 cell program were increased, including Ager, Rtkn2, Lima1, Tead4, Cttnbp2 , and Mslnl , consistent with the increased number of AT1 cells (Figure 3A, C); however, a number of genes associated with AT1 cells were downregulated in both the bulk and single cell data including Fbln5, Bmp4, Slco3a1, Samhd1, Slc4a5 , and Gnb4 .…”

“…7,49,56,57,67 Impaired commitment to the AT2 cell lineage was previously observed in animals deficient in epithelial FGFR2B signaling during the late pseudo glandular period. 47,48,68 Chromatin accessibility at the Fgfr2b locus was altered in Prdm3/16 deficient epithelial cells accompanied by a reduction in the expression of Fgfr2b and one of its known targets, Etv5 , also known to be critical for AT2 cell specification. 57,68 The similarity in phenotype between these studies targeting signal transduction and chromatin regulation is provocative, suggesting identification of the precise integration of intercellular signaling with activity of chromatin complexes in modulating activity of partner transcription factors is an area of high priority for future studies.…”

Postnatal FGFR-signaling establishes gradients of secretory cell identities along the proximal-distal axis of the lung airways

“…Fibroblast growth factor (FGF) signalling is crucial for lung epithelial branching 70 and is later required for AEC2 differentiation and maintenance [50][51][52][71][72][73] . Our gene expression analysis showed that Fgfr2 is also expressed in the adult epithelial cells belonging to gene module-1, which shows high levels in AEC2 and DP-cells and gradually decreases in S2 and S1 airway cells (Suppl.…”