Senescence of Alveolar Stem Cells Drives Progressive Pulmonary Fibrosis

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

doi:10.2139/ssrn.3438364

Cited by 9 publications

(17 citation statements)

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“…A prevailing concept is that AT2 depletion potentially through repetitive microinjuries is the underlying cause of lung fibrosis [5]. Indeed, targeted deletion of AT2 cells is sufficient to induce a fibrotic response in the lungs, but it is not sustained [36,37]. Additional data supporting this idea of stem cell exhaustion is that the number of AT2 cells are diminished in IPF lungs [38,39].…”

Section: At2 Depletion In Idiopathic Pulmonary Fibrosis (Ipf)mentioning

confidence: 99%

“…Furthermore, dysfunctional AT2 cells in the fibrotic lung also produce pro-fibrotic factors that contribute to fibrogenesis [24]. Altogether, AT2 cells are not just simply depleted in the fibrotic lung as collateral damage to ongoing injury, but in addition, these cells have acquired a dysfunctional phenotype that places it as a central driver of fibrosis [37] as depicted in Figure 2. AT2 plasticity has been best demonstrated by the ability of TGFβ to alter their cellular phenotype [86][87][88].…”

Section: At2 Dysfunction In Ipfmentioning

confidence: 99%

“…As such, both ER stress and telomere dysfunction, both of which have the potential to activate a program of cellular senescence, have been found to impair differentiation by stem cells [92][93][94][95][96]. Emerging evidence also demonstrates that induction of AT2 senescence in itself is sufficient to promote lung fibrosis [37].…”

Section: At2 Dysfunction In Ipfmentioning

confidence: 99%

“…Cellular senescence, one of the signature characterizations of the aging process, plays an important role in the pathogenesis of lung fibroproliferative disorders [97][98][99]. Fibrotic regions of lung tissue from IPF patients show both regional depletion of AT2 cells and the presence of AT2 cells with a senescent-like phenotype [37,38]. As such, AT2 senescence may have a limited reparative capacity that contributes to the fibroproliferation [22,100].…”

Section: Impaired At2 Self-renewal In Ipfmentioning

confidence: 99%

“…AT2 senescence plays a prominent role in lung fibrosis through the acquisition of a senescence-associated secretory phenotype (SASP) and is a feature of senescent cells that result in the release of a myriad of factors with inflammatory and fibrogenic properties [187]. AT2 cells within the lungs of IPF patients and bleomycin-injured mice gain features consistent with a SASP [37,38,93,125,126]. Indeed, a number of secreted inflammatory and profibrotic factors are released from AT2 cells within the fibrotic lung that can have autocrine and paracrine actions within the fibrotic microenvironment to promote lung fibrosis [24].…”

Section: The Senescence-associated Secretory Phenotype Has Pro-fibrotmentioning

confidence: 99%

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Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Parimon

Yao

Stripp

et al. 2020

IJMS

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215

133

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: Alveolar epithelial type II cells (AT2) are a heterogeneous population that have critical secretory and regenerative roles in the alveolus to maintain lung homeostasis. However, impairment to their normal functional capacity and development of a pro-fibrotic phenotype has been demonstrated to contribute to the development of idiopathic pulmonary fibrosis (IPF). A number of factors contribute to AT2 death and dysfunction. As a mucosal surface, AT2 cells are exposed to environmental stresses that can have lasting effects that contribute to fibrogenesis. Genetical risks have also been identified that can cause AT2 impairment and the development of lung fibrosis. Furthermore, aging is a final factor that adds to the pathogenic changes in AT2 cells. Here, we will discuss the homeostatic role of AT2 cells and the studies that have recently defined the heterogeneity of this population of cells. Furthermore, we will review the mechanisms of AT2 death and dysfunction in the context of lung fibrosis.

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Section: At2 Depletion In Idiopathic Pulmonary Fibrosis (Ipf)mentioning

confidence: 99%

Section: At2 Dysfunction In Ipfmentioning

confidence: 99%

Section: At2 Dysfunction In Ipfmentioning

confidence: 99%

Section: Impaired At2 Self-renewal In Ipfmentioning

confidence: 99%

Section: The Senescence-associated Secretory Phenotype Has Pro-fibrotmentioning

confidence: 99%

See 3 more Smart Citations

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Parimon

Yao

Stripp

et al. 2020

IJMS

Self Cite

215

133

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Chronic WNT/β-catenin signaling induces cellular senescence in lung epithelial cells

Lehmann

Hu²,

et al. 2020

Cellular Signalling

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The rapid expansion of the elderly population has led to the recent epidemic of agerelated diseases, including increased incidence and mortality of chronic lung diseases, such as Idiopathic Pulmonary Fibrosis (IPF). Cellular senescence is a major hallmark of aging and has a higher occurrence in IPF. The lung epithelium represents a major site of tissue injury, cellular senescence and aberrant activity of developmental pathways such as the WNT/β-catenin pathway in IPF. The potential impact of WNT/β-catenin signaling on alveolar epithelial senescence in general as well as in IPF, however, remains elusive. Here, we characterized alveolar epithelial cells of aged mice and assessed the contribution of chronic WNT/β-catenin signaling on alveolar epithelial type (AT) II cell senescence. Whole lungs from old (16-24 months) versus young (3 months) mice had relatively less epithelial (EpCAM + ) but more inflammatory (CD45 + ) cells, as assessed by flow cytometry. Compared to young ATII cells, old ATII cells showed decreased expression of the ATII cell marker Surfactant Protein C along with increased expression of the ATI cell marker Hopx, accompanied by increased WNT/β-catenin activity. Notably, when placed in an organoid assay, old ATII cells exhibited decreased progenitor cell potential. Chronic

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Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis

et al. 2020

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The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single cell RNA-seq of the bleomycin lung injury model, we resolved transcriptional dynamics for 28 cell types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8 + transitional stem cell state during alveolar regeneration. These cells have squamous morphology, feature p53 and NFkB activation and display transcriptional features of cellular senescence. The Krt8+ state appears in several independent models of lung injury and persists in human lung fibrosis, creating a distinct cell-cell communication network with mesenchyme and macrophages during repair. We generated a model of gene regulatory programs leading to Krt8+ transitional cells and their terminal differentiation to alveolar type-1 cells. We propose that in lung fibrosis, perturbed molecular checkpoints on the way to terminal differentiation can cause aberrant persistence of regenerative intermediate stem cell states.

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Senescence of Alveolar Stem Cells Drives Progressive Pulmonary Fibrosis

Cited by 9 publications

References 0 publications

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Chronic WNT/β-catenin signaling induces cellular senescence in lung epithelial cells

Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis

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