scholarly journals Senescence of alveolar stem cells drives progressive pulmonary fibrosis

2019 ◽  
Author(s):  
Changfu Yao ◽  
Xiangrong Guan ◽  
Gianni Carraro ◽  
Tanyalak Parimon ◽  
Xue Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Chronic Disease ◽  
Pulmonary Fibrosis ◽  
Cellular Senescence ◽  
Adult Mouse ◽  
Alveolar Type ◽  
Epithelial Stem Cells ◽  
Organ Function ◽  
P53 Activation

AbstractTissue fibrosis is a common pathological outcome of chronic disease that markedly impairs organ function leading to morbidity and mortality. In the lung, idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Here, we show that alveolar type 2 (AT2) stem cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of epithelial stem cells serves as a proximal driver of Tgfβ activation and progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation, senescence, or downstream Tgfβ activation, block fibrogenesis.

scholarly journals Regulation of alveolar type 2 stem/progenitor cells in lung injury and regeneration

2020 ◽  
Vol 52 (7) ◽  
pp. 716-722 ◽  
Author(s):  
Ailing Wu ◽  
Hai Song
Keyword(s):  
Stem Cells ◽  
Lung Injury ◽  
Progenitor Cells ◽  
Alveolar Epithelium ◽  
Lung Epithelial Cells ◽  
Alveolar Type ◽  
Epithelial Stem Cells ◽  
Lung Structure ◽  
And Function

Abstract The renewal of lung epithelial cells is normally slow unless the lung is injured. The resident epithelial stem cells rapidly proliferate and differentiate to maintain lung structure and function when the lung is damaged. The alveolar epithelium is characterized by alveolar type 1 (AT1) and alveolar type 2 (AT2) cells. AT2 cells are the stem cells for alveoli, as they can both self-renew and generate AT1 cells. Abnormal proliferation and regulation of AT2 cells will lead to serious lung diseases including cancers. In this review, we focused on the alveolar stem/progenitor cells, the key physiological function of AT2 cells in lung homeostasis and the complicated regulation of AT2 cells in the repairing processes after lung injury.

scholarly journals Decreased expression of Met during differentiation in rat lung

2016 ◽  
Vol 60 (1) ◽  
Author(s):  
T. Kato ◽  
K. Oka ◽  
T. Nakamura ◽  
A. Ito
Keyword(s):  
Stem Cells ◽  
3D Culture ◽  
Immunofluorescence Assay ◽  
Lung Epithelial Cells ◽  
Alveolar Type ◽  
Cell Marker ◽  
Epithelial Stem Cells ◽  
Club Cell ◽  
Adult Mice ◽  
Lung Epithelial

<p>Organ-specific stem cells play key roles in maintaining the epithelial cell layers of lung. Bronchioalveolar stem cells (BASCs) are distal lung epithelial stem cells of adult mice. Alveolar type 2 (AT2) cells have important functions and serve as progenitor cells of alveolar type 1 (AT1) cells to repair the epithelium when they are injured. Hepatocyte growth factor (HGF) elicits mitogenic, morphogenic, and anti-apoptotic effects on lung epithelial cells through tyrosine phosphorylation of Met receptor, and thus is recognized as a pulmotrophic factor. To understand which cells HGF targets in lung, we identified the cells expressing Met by immunofluorescence assay. Met was strongly expressed in BASCs, which expressed an AT2 cell marker, pro-SP-C, and a club cell marker, CCSP. In alveoli, we found higher expression of Met in primary AT2 than in AT1 cells, which was confirmed using primary AT2 cells. We further examined the mitogenic activity of HGF in AT2-cell-derived alveolar-like cysts (ALCs) in 3D culture. Multicellular ALCs expressed Met, and HGF enhanced the ALC production. Taking these findings together, BASCs could also be an important target for HGF, and HGF-Met signaling could function more potent on cells that have greater multipotency in adult lung.</p>

Inhibition of Wnt/β-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury

2014 ◽  
Vol 307 (3) ◽  
pp. C234-C244 ◽  
Author(s):  
Cong Wang ◽  
Huiming Zhu ◽  
Zhaorui Sun ◽  
Zou Xiang ◽  
Yuanyuan Ge ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Epithelial Differentiation ◽  
Unknown Etiology ◽  
Alveolar Type ◽  
Coculture System

Idiopathic pulmonary fibrosis is a progressive lung disorder of unknown etiology. Previous studies have shown that aberrant activation of the Wnt/β-catenin signaling cascade occurs in lungs of patients with idiopathic pulmonary fibrosis. Given the important roles of the Wnt/β-catenin signaling pathway in the development of pulmonary fibrosis, we targeted this pathway for the intervention of pulmonary fibrosis with XAV939, a small molecule that specifically inhibits Tankyrase 1/2, eventually leading to the degradation of β-catenin and suppression of the Wnt/β-catenin signaling pathway. Our results demonstrated that XAV939 significantly inhibited the activation of Wnt/β-catenin signaling and attenuated bleomycin-induced lung fibrosis in mice, and thus improved the survival of mice with lung injury. Interestingly, previous investigations have confirmed that endogenous and exogenous mesenchymal stem cells could be recruited to the injured lung, although the exact effects of these cells are debatable. To determine the effect of Wnt/β-catenin signaling in the epithelial differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs), we established a coculture system that contains BM-MSCs and alveolar type II epithelial cells. The in vitro experiments demonstrated that XAV939 could promote the differentiation of BM-MSCs into an epithelium-like phenotype in the coculture system. We also found that XAV939 could inhibit the proliferation and myofibroblast differentiation of NIH/3T3 fibroblasts. This work supports that inhibition of the Wnt/β-catenin signaling pathway may be exploited for the treatment of idiopathic pulmonary fibrosis for which effective treatment strategies are still lacking.

scholarly journals How the Pathological Microenvironment Affects the Behavior of Mesenchymal Stem Cells in the Idiopathic Pulmonary Fibrosis

2020 ◽  
Vol 21 (21) ◽  
pp. 8140
Author(s):  
Martina Bonifazi ◽  
Mariangela Di Vincenzo ◽  
Miriam Caffarini ◽  
Federico Mei ◽  
Michele Salati ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Chronic Disease ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cell Types ◽  
And Control ◽  
And Oxidative Stress

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by fibroblasts activation, ECM accumulation, and diffused alveolar inflammation. The role of inflammation in IPF is still controversial and its involvement may follow nontraditional mechanisms. It is seen that a pathological microenvironment may affect cells, in particular mesenchymal stem cells (MSCs) that may be able to sustain the inflamed microenvironment and influence the surrounding cells. Here MSCs have been isolated from fibrotic (IPF-MSCs) and control (C-MSCs) lung tissue; first cells were characterized and compared by the expression of molecules related to ECM, inflammation, and other interdependent pathways such as hypoxia and oxidative stress. Subsequently, MSCs were co-cultured between them and with NHLF to test the effects of the cellular crosstalk. Results showed that pathological microenvironment modified the features of MSCs: IPF-MSCs, compared to C-MSCs, express higher level of molecules related to ECM, inflammation, oxidative stress, and hypoxia; notably, when co-cultured with C-MSCs and NHLF, IPF-MSCs are able to induce a pathological phenotype on the surrounding cell types. In conclusion, in IPF the pathological microenvironment affects MSCs that in turn can modulate the behavior of other cell types favoring the progression of IPF.

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