Senescence of alveolar stem cells drives progressive pulmonary fibrosis
Posted on: 8 November 2019
Preprint posted on 28 October 2019
In pulmonary fibrosis, alveolar type II stem cells become senescent. In a mouse model, genetic induction of senescence in this population was sufficient to cause TGFβ-dependent progressive fibrosis, in contrast to existing rapidly resolving models.
Selected by Rob Hynds
Categories: cell biology, molecular biology, pathology
Background
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with a median survival of 3 years and an increasing incidence. The epithelium that lines the alveoli, the gas exchange units of the lung, consists of alveolar type I (ATI) and alveolar type II (ATII) cells, which provide a surface for gas exchange and produce pulmonary surfactant, respectively. Alveolar type II cells also serve as facultative epithelial stem cells, transitioning from their specialized role in production of surfactant to a regenerative role in response to normal tissue maintenance or repair following injury. There is persuasive evidence that dysfunctional epithelial-mesenchymal cross-talk underlies IPF pathogenesis. Previous studies have shown an association between cellular senescence and tissue remodelling in IPF and that ablation of senescent cells can improve outcome in the mouse bleomycin lung injury model. However, the cell types that mediate these effects are unknown.
Key Findings
In a published transcriptomics dataset and by using senescence-associated β-galactosidase (SA-β-gal) staining, Yao et al. confirm the senescent phenotype of IPF patient epithelial cells. Then, in an ATII-enriched RNAseq dataset and a new epithelial cell single cell RNAseq experiment, the authors demonstrate that ATII cells themselves have the transcriptomic hallmarks of senescence in IPF. Immunofluorescence confirmed expression of the cell cycle inhibitors p16 and p21 in ATII cells in fibrotic regions of IPF lung. In the bleomycin-induced mouse lung injury model – which produces an acute fibrotic lung injury – ATII cells also upregulated transcription of senescence-associated genes.
Next, the authors develop a mouse model in which conditional loss of Sin3a – a component of the SIN3A/HDAC co-repressor complex – in ATII cells induces p53-dependent senescence. Loss of Sin3a impaired progenitor function in colony forming assays, increased cellular size and transcriptomic comparison of WT and Sin3a-/- ATII cells revealed widespread activation of senescence-associated processes. Immunofluorescence and SA-β-gal staining confirmed the senescent phenotype of Sin3a-/- ATII cells.
After ATII-specific Sin3a loss, mice developed peripheral deposition of extracellular matrix proteins that progressed inward over time. Bulk RNAseq experiments showed fibrosis- and senescence-associated gene expression in these lungs and protein level validation shows fibrotic disease featuring myofibroblast differentiation and collagen deposition. Consistent with senescent epithelial cells driving fibrosis in this model, p53 and TGFβ emerge as key candidate regulators from transcriptomic datasets. p53 deletion on top of Sin3a loss protected mice from the morbidity and mortality associated with Sin3a loss alone and reduced the extent of both senescence and fibrosis. A TGFβ activation score was highest in cells with Sin3a loss and pharmacologic inhibition of the TGFβ pathway using the small molecule SB431542 protected against morbidity and mortality, reduced the extent of fibrosis but did not reduce the extent of senescence, suggesting that TGFβ activation is downstream of ATII senescence. Importantly, treatment with the senolytic drugs dasatinib and quercetin led to protection of mice with Sin3a loss from morbidity and mortality and also reduced the extent of both senescence and fibrosis, placing senescence as the central mediator of fibrosis in this model.
To compare loss of ATII cells to ATII cell senescence, the authors compared their ATII cell-specific Sin3a loss model to ATII depletion using diphtheria toxin A expression from the same Cre driver. While initial fibrosis is seen in both models, mice with DTA-induced ATII loss recover and do not show progressive fibrosis, thus ATII phenotype, rather than functional loss of ATII cells, seems to drive fibrosis.
Conclusions
Overall, this work shows that senescence of ATII cells occurs in pulmonary fibrosis patient lungs and develops a cell type-specific model to determine the effect of ATII cell senescence. p53-dependent senescence drives progressive lung fibrosis through a TGFβ-dependent mechanism.
Questions for the authors
Q1. Using their single cell RNA sequencing resource, do the authors have a sense of the extent to which the senescence phenotype might be enriched in ATII cells vs other epithelial cells in the IPF lung? A relative senescence index might be interesting?
Q2. Are there fewer ATII cells in fibrotic lungs and is it possible that senescence also drives stem cell loss, e.g. through altered differentiation?
Q3. How extensive is ATII cell loss in the DTA model? Is there any concomitant improvement of the epithelial injury or expansion of ‘ATII-like’ cells during fibrotic resolution?
doi: https://doi.org/10.1242/prelights.15008
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