Release of Notch activity coordinated by IL-1β signalling confers differentiation plasticity of airway progenitors via Fosl2 during alveolar regeneration

Abstract

While the acquisition of cellular plasticity in adult stem cells is essential for rapid regeneration after tissue injury, little is known about the underlying mechanisms governing this process. Our data reveal the coordination of airway progenitor differentiation plasticity by inflammatory signals during alveolar regeneration. Upon damage, IL-1β signalling-dependent modulation of Jag1/2 expression in ciliated cells results in the inhibition of Notch signalling in secretory cells, which drives reprogramming and acquisition of differentiation plasticity. We identify a transcription factor Fosl2/Fra2 for secretory cell fate conversion to alveolar type 2 (AT2) cells retaining the distinct genetic and epigenetic signatures of secretory lineages. We furthermore reveal that KDR/FLK-1 + human secretory cells display a conserved capacity to generate AT2 cells via Notch inhibition. Our results demonstrate the functional role of a IL-1β-Notch-Fosl2 axis for the fate decision of secretory cells during injury repair, proposing a potential therapeutic target for human lung alveolar regeneration.

Airway secretory cell fate conversion via YAP‐mTORC1‐dependent essential amino acid metabolism

“…Therefore, we aimed to evaluate the functional role of EAAs in directing the fate conversion of secretory cells into DATP‐AT1 cells using an ex vivo three‐dimensional (3D) organoid culture system. We recently identified KDR/FLK1 as the surface marker of airway secretory cells (Choi et al , 2021 ; Jiang et al , 2021 ). Using this marker, we isolated secretory cells (KDR + EpCAM + ) from Lats1/2 dKO lungs, followed by organoid coculture with stromal cells (Fig 3B ).…”

Abnormal respiratory progenitors in fibrotic lung injury

“…Using a Sftpc + ATII depletion mouse model, it was concluded that there are more Sftpc + ATII cells derived from alveolar ATII cells than from BASCs [ 15 ]. However, a recent study found that mouse Scgb1a1 derived Sftpc + BASCs (also termed secretory ATII cells, sAT2 cells) are capable of long-term self-renewal, more so than residual AT2 cells in in vitro organoids [ 16 ]. It remains unknown in lung fibrosis if ATII cell depletion occurs within fibrotic area or if BASCs or the remaining ATII cells are the major source for regeneration of ATII cells in the alveoli.…”

“…Besides BASCs, studies have shown that club cells [ 3 ], BCs, integrin α6β4 positive cells, H2-K1 high, and Uroplakin3a ( Upk3a ) expressing airway epithelial progenitors can migrate to the alveoli and give rise to ATII cells under conditions of severe injury that involve broad epithelial denudation [ 17 – 21 ]. An abnormal cluster of Fstl1 + secretory cells were found during defective club cells (or secretory cells) transition to ATII cells [ 16 ]. These cells were marked by Id3, Porcn , and Cdkn1c and blocked the fate conversion from secretory to ATII cells when lacking sustained Notch activity.…”

“…Further, Wnt activity antagonized Notch signaling to favor LNEPs differentiation into ATII cells for recovery [ 19 , 29 ]. In addition, Notch inhibition skews the differentiation of human secretory cells ( CC10 + KDR + HTII280 − ) into ATII cells instead of ciliated cells and BCs in culture conditions [ 16 ]. Recent scRNA-seq mapping of epithelial cell types for normal and IPF human airways suggested that BC subpopulations constitute a hierarchy regulated by Notch signaling.…”

“…It is reported that macrophage derived IL1β activated a subpopulation of primed ATII cells expressing IL1R1 for differentiation into DATPs, while chronic IL1β halted DATPs transition into functional ATI cells, which results in impaired alveolar regeneration in fibrotic lung [ 10 ]. The same group did follow-up research and found that IL1β signaling through IL1R1 on ciliated cells via paracrine Notch ligands, JAG1 and JAG2, is essential for secretory cell differentiation of ATII cells [ 16 ]. These studies suggest that inflammatory signals are required for ATII cell mediated alveolar regeneration but sustained inflammatory response can cause defects for generating functional alveolar niche following injury.…”