Senescence of alveolar stem cells drives progressive pulmonary fibrosis

Yao, Changfu; Guan, Xiangrong; Carraro, Gianni; Parimon, Tanyalak; Li, Xue; Huang, Guanling; Soukiasian, Harmik J.; Gourichon, David; Weigt, S. Samuel; Belperio, John A.; Chen, Peter; Jiang, Dianhua; Noble, Paul W.; Stripp, Barry R.

doi:10.1101/820175

Cited by 20 publications

(26 citation statements)

References 105 publications

(110 reference statements)

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“…These cells are characterized by a phenotype reminiscent of cellular senescence and upregulation of a gene expression signature called the "senescence-associated secretory phenotype" (SASP), although the signature is not specific to senescence and may be a general indicator of epithelial dysfunction. (42)(43)(44) This signature is upregulated in epithelial cells after bleomycin injury and decreased after KIRA8 treatment (Fig 1H and I). One key marker in this signature is Cdkn1a, which encodes p21, a cyclin dependent kinase inhibitor that induces cell cycle arrest and is a canonical marker of senescent cells.…”

Section: Ire1α Acts On the Pulmonary Epithelium To Promote Fibrosismentioning

confidence: 90%

IRE1α drives lung epithelial progenitor dysfunction to establish a niche for pulmonary fibrosis

Auyeung¹,

Downey²,

Kathiriya³

et al. 2021

Preprint

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Idiopathic pulmonary fibrosis (IPF) is a disease of progressive interstitial fibrosis, which leads to severe debilitation, respiratory failure, and death. In IPF, environmental exposures interact with genetic risk factors to engender critical patho-etiological events in lung epithelial cells, including endoplasmic reticulum (ER) stress and TGFβ signaling, but the interactions between these disparate pathways are not well understood. We previously showed that kinase inhibitors of the IRE1α bifunctional kinase/RNase—a central mediator of the unfolded protein response (UPR) to ER stress—protected mice from bleomycin-induced pulmonary fibrosis. Here we show that a nanomolar-potent, mono-selective kinase inhibitor of IRE1α (KIRA8) decreases ER-stress induced TGFβ signaling and the senescence-associated secretory phenotype (SASP) in the lung epithelium after bleomycin exposure. A recently-described subset of "damage-associated transient progenitors" (DATPs) display IRE1α-regulated pathological gene signatures that are quelled by KIRA8, in vivo. After injury, these cells uniquely express integrin αvβ6, a key activator of TGFβ in pulmonary fibrosis. KIRA8 inhibition of IRE1α decreases both DATP number and Itgb6 expression in remaining cells, with a decrease in local collagen accumulation. Single-cell RNA sequencing from IPF lungs revealed an analogous Itgb6+ cell population that may also be regulated by IRE1α. These findings suggest that lung epithelial progenitor cells sit at the center of the fibrotic niche, and IRE1α signaling locks them into a dysfunctional state that establishes and perpetuates pathological fibrosis.

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Section: Ire1α Acts On the Pulmonary Epithelium To Promote Fibrosismentioning

confidence: 90%

IRE1α drives lung epithelial progenitor dysfunction to establish a niche for pulmonary fibrosis

Auyeung¹,

Downey²,

Kathiriya³

et al. 2021

Preprint

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“…In conclusion, senescence and SASP signals seem to modulate the epithelial-mesenchymal crosstalk in an unsuccessful attempt at repair in the lung, highlighting their important role in the pathobiology of IPF. Consistently, depletion of senescent cells using senolytic drugs or genetic models has a beneficial effect against fibrosis and other age-related diseases in mice [29,30,51,60]. However, some ( pre-)senescent cells seem to be essential for homeostasis and repair in the mouse [61,62], highlighting the importance of understanding how cell-type-specific senescence modulates IPF.…”

Section: Regeneration Of a Diseased Lung Chronic Diseasesmentioning

confidence: 95%

“…Additionally, re-epithelialisation of the lung is compromised by reprogramming of AT2 cells along with the acquisition of mesenchymal markers partially induced by ER-dependent TGF-β activation [50]. Furthermore, senescent AT2 cells induce a fibroblast-to-myofibroblast transition (FMT) in surrounding fibroblasts via TGF-β1 [51], Nanog [52], mTOR [53] and Wnt [40,42] pathways, processes that have been related to exaggerated ECM deposition in IPF lungs [54,55].…”

Section: Regeneration Of a Diseased Lung Chronic Diseasesmentioning

confidence: 99%

Lung regeneration: implications of the diseased niche and ageing

et al. 2020

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Most chronic and acute lung diseases have no cure, leaving lung transplantation as the only option. Recent work has improved our understanding of the endogenous regenerative capacity of the lung and has helped identification of different progenitor cell populations, as well as exploration into inducing endogenous regeneration through pharmaceutical or biological therapies. Additionally, alternative approaches that aim at replacing lung progenitor cells and their progeny through cell therapy, or whole lung tissue through bioengineering approaches, have gained increasing attention. Although impressive progress has been made, efforts at regenerating functional lung tissue are still ineffective. Chronic and acute lung diseases are most prevalent in the elderly and alterations in progenitor cells with ageing, along with an increased inflammatory milieu, present major roadblocks for regeneration. Multiple cellular mechanisms, such as cellular senescence and mitochondrial dysfunction, are aberrantly regulated in the aged and diseased lung, which impairs regeneration. Existing as well as new human in vitro models are being developed, improved and adapted in order to study potential mechanisms of lung regeneration in different contexts. This review summarises recent advances in understanding endogenous as well as exogenous regeneration and the development of in vitro models for studying regenerative mechanisms.

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“…In bleomycin-challenged mice, distal lung epithelial cells increase expression of profibrotic SASP factors, including MCP-1, matrix metalloproteinases, and TGF-β (105). Recent modeling of AT2 senescence by conditional deletion of Sin3a, a key component of the Sin3-HDAC complex, resulted in p53-dependent cellular senescence, AT2 cell depletion, and TGF-β-dependent spontaneous pulmonary fibrosis, further linking AT2 SASP signaling to fibrosis (106).…”

Section: Epithelial Participation In Ipf Crosstalk Networkmentioning

confidence: 99%