scholarly journals miR-200 family members reduce senescence and restore idiopathic pulmonary fibrosis type II alveolar epithelial cell transdifferentiation

2019 ◽  
Vol 5 (4) ◽  
pp. 00138-2019 ◽  
Author(s):  
Silvia Moimas ◽  
Francesco Salton ◽  
Beata Kosmider ◽  
Nadja Ring ◽  
Maria C. Volpe ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Family Members ◽  
Alveolar Type ◽  
Type I ◽  
Cell Renewal ◽  
Type Ii ◽  
Mesenchymal Transition ◽  
Marker Expression ◽  
Emt Markers

RationaleAlveolar type II (ATII) cells act as adult stem cells contributing to alveolar type I (ATI) cell renewal and play a major role in idiopathic pulmonary fibrosis (IPF), as supported by familial cases harbouring mutations in genes specifically expressed by these cells. During IPF, ATII cells lose their regenerative potential and aberrantly express pathways contributing to epithelial–mesenchymal transition (EMT). The microRNA miR-200 family is downregulated in IPF, but its effect on human IPF ATII cells remains unproven. We wanted to 1) evaluate the characteristics and transdifferentiating ability of IPF ATII cells, and 2) test whether miR-200 family members can rescue the regenerative potential of fibrotic ATII cells.MethodsATII cells were isolated from control or IPF lungs and cultured in conditions promoting their transdifferentiation into ATI cells. Cells were either phenotypically monitored over time or transfected with miR-200 family members to evaluate the microRNA effect on the expression of transdifferentiation, senescence and EMT markers.ResultsIPF ATII cells show a senescent phenotype (p16 and p21), overexpression of EMT (ZEB1/2) and impaired expression of ATI cell markers (AQP5 and HOPX) after 6 days of culture in differentiating medium. Transfection with certain miR-200 family members (particularly miR-200b-3p and miR-200c-3p) reduced senescence marker expression and restored the ability to transdifferentiate into ATI cells.ConclusionsWe demonstrated that ATII cells from IPF patients express senescence and EMT markers, and display a reduced ability to transdifferentiate into ATI cells. Transfection with certain miR-200 family members rescues this phenotype, reducing senescence and restoring transdifferentiation marker expression.

scholarly journals Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis

2011 ◽  
Vol 301 (1) ◽  
pp. L71-L78 ◽  
Author(s):  
Cecilia Marmai ◽  
Rachel E. Sutherland ◽  
Kevin K. Kim ◽  
Gregory M. Dolganov ◽  
Xiaohui Fang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Mesenchymal Cells ◽  
Alveolar Type ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii ◽  
Alveolar Type Ii Cells ◽  
Mesenchymal Transition

Prior work has shown that transforming growth factor-β (TGF-β) can mediate transition of alveolar type II cells into mesenchymal cells in mice. Evidence this occurs in humans is limited to immunohistochemical studies colocalizing epithelial and mesenchymal proteins in sections of fibrotic lungs. To acquire further evidence that epithelial-to-mesenchymal transition occurs in the lungs of patients with idiopathic pulmonary fibrosis (IPF), we studied alveolar type II cells isolated from fibrotic and normal human lung. Unlike normal type II cells, type II cells isolated from the lungs of patients with IPF express higher levels of mRNA for the mesenchymal proteins type I collagen, α-smooth muscle actin (α-SMA), and calponin. When cultured on Matrigel/collagen, human alveolar type II cells maintain a cellular morphology consistent with epithelial cells and expression of surfactant protein C (SPC) and E-cadherin. In contrast, when cultured on fibronectin, the human type II cells flatten, spread, lose expression of pro- SPC, and increase expression of vimentin, N-cadherin, and α-SMA; markers of mesenchymal cells. Addition of a TGF-β receptor kinase inhibitor (SB431542) to cells cultured on fibronectin inhibited vimentin expression and maintained pro-SPC expression, indicating persistence of an epithelial phenotype. These data suggest that alveolar type II cells can acquire features of mesenchymal cells in IPF lungs and that TGF-β can mediate this process.

scholarly journals Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Eleanor Valenzi ◽  
Tracy Tabib ◽  
Anna Papazoglou ◽  
John Sembrat ◽  
Humberto E. Trejo Bittar ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Single Cell ◽  
Alveolar Type ◽  
Type I ◽  
Interferon Signaling ◽  
Mesenchymal Transition

Idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) differ in the predominant demographics and identified genetic risk alleles of effected patients, however both diseases frequently progress to respiratory failure and death. Contrasting advanced SSc-ILD to IPF provides insight to the role dysregulated immunity may play in pulmonary fibrosis. To analyze cell-type specific transcriptome commonalities and differences between IPF and SSc-ILD, we compared single-cell RNA-sequencing (scRNA-seq) of 21 explanted lung tissue specimens from patients with advanced IPF, SSc-ILD, and organ donor controls. Comparison of IPF and SSc-ILD tissue identified divergent patterns of interferon signaling, with interferon-gamma signaling upregulated in the SPP1hi and FABP4hi macrophages, cytotoxic T cells, and natural kill cells of IPF, while type I interferon signaling and production was upregulated in the corresponding SSc-ILD populations. Plasmacytoid dendritic cells were found in diseased lungs only, and exhibited upregulated cellular stress pathways in SSc-ILD compared to IPF. Alveolar type I cells were dramatically decreased in both IPF and SSc-ILD, with a distinct transcriptome signature separating these cells by disease. KRT5-/KRT17+ aberrant basaloid cells exhibiting markers of cellular senescence and epithelial-mesenchymal transition were identified in SSc-ILD for the first time. In summary, our study utilizes the enriched capabilities of scRNA-seq to identify key divergent cell types and pathways between IPF and SSc-ILD, providing new insights into the shared and distinct mechanisms between idiopathic and autoimmune interstitial lung diseases.

scholarly journals TM4SF5-mediated CD44v8-10 splicing variant promotes survival of type II alveolar epithelial cells during idiopathic pulmonary fibrosis

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Ji Eon Kim ◽  
Hye-Jin Kim ◽  
Jae Woo Jung ◽  
Dae-Geun Song ◽  
Dasomi Park ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cell Fate ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Type I ◽  
Type Ii ◽  
Alveolar Epithelial ◽  
Primary Mouse

Abstract Reactive oxygen species (ROS) regulate cell fate, although signaling molecules that regulate ROS hormesis remain unclear. Here we show that transmembrane 4 L six family member 5 (TM4SF5) in lung epithelial cells induced the alternatively spliced CD44v8-10 variant via an inverse ZEB2/epithelial splicing regulatory proteins (ESRPs) linkage. TM4SF5 formed complexes with the cystine/glutamate antiporter system via TM4SF5- and CD44v8-10-dependent CD98hc plasma-membrane enrichment. Dynamic TM4SF5 binding to CD98hc required CD44v8-10 under ROS-generating inflammatory conditions. TM4SF5 and CD44v8-10 upregulated cystine/glutamate antiporter activity and intracellular glutathione levels, leading to ROS modulation for cell survival. Tm4sf5-null mice exhibited attenuated bleomycin-induced pulmonary fibrosis with lower CD44v8-10 and ESRPs levels than wild-type mice. Primary mouse alveolar epithelial cells (AECs) revealed type II AECs (AECII), but not type I, to adapt the TM4SF5-mediated characteristics, suggesting TM4SF5-mediated AECII survival following AECI injury during idiopathic pulmonary fibrosis (IPF). Thus, the TM4SF5-mediated CD44v8-10 splice variant could be targeted against IPF.

scholarly journals Mechanism of lipopolysaccharide-mediated induction of epithelial-mesenchymal transition of alveolar type II epithelial cells in absence of other inflammatory cells

2021 ◽  
Vol 19 ◽  
pp. 205873922110144
Author(s):  
Shuai Wu ◽  
Huan Ye ◽  
TianJiao Xue ◽  
Jiali Wang
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Cell ◽  
Expression Level ◽  
Alveolar Type ◽  
Type Ii ◽  
Gram Negative ◽  
Mesenchymal Transition ◽  
Tgf Β1

Several studies have shown that gram-negative bacilli infection can cause acute lung injury, and that consequent pulmonary fibrosis is caused when alveolar type-II epithelial cells undergo epithelial-mesenchymal transition (EMT). However, the mechanism underlying this change remains unclear. This study aimed to elucidate whether the main toxin of gram-negative bacteria, lipopolysaccharide (LPS), can induce EMT in human alveolar epithelial cells, and the underlying molecular mechanisms. Human alveolar type-II epithelial cells (A549) were used in EMT induction experiments. Cells were collected after LPS exposure, and changes in the expression levels of epithelial and mesenchymal cell markers were determined. Further, the effect of LPS exposure on the expression of Toll-like Receptor 4 (TLR4), Transforming Growth Factor-beta 1 (TGF-β1) and Smad2/3 was assessed. The expression level of a mesenchymal cell marker was also assessed after pharmacological inhibition of TLR4 and TGF-β1 prior to addition of LPS, to identify downstream pathways involved in EMT induction. Results showed that LPS exposure caused significant downregulation of epithelial marker E-cadherin, and upregulation of mesenchymal marker vimentin, together with increased expression of TGF-β1 and activation of the TGF-β1/Smad2/3 pathway. Furthermore, pretreatment with TGF-β1 and TLR4 inhibitors suppressed EMT, and treatment with the latter also reduced the expression level of TGF-β1. Overall, we conclude that LPS directly induces EMT in A549 cells through upregulation of TLR4 and activation of the TGF-β1/Smad2/3 signalling pathway. Our results suggest that LPS-mediated pulmonary fibrosis may occur in ALI patients even if the LPS-induced inflammatory response is inhibited.

Safety and Tolerability of Alveolar Type II Cell Transplantation in Idiopathic Pulmonary Fibrosis

CHEST Journal ◽  
2016 ◽  
Vol 150 (3) ◽  
pp. 533-543 ◽  
Author(s):  
Anna Serrano-Mollar ◽  
Gemma Gay-Jordi ◽  
Raquel Guillamat-Prats ◽  
Daniel Closa ◽  
Fernanda Hernandez-Gonzalez ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cell Transplantation ◽  
Alveolar Type ◽  
Type Ii ◽  
Alveolar Type Ii Cell ◽  
Type Ii Cell

scholarly journals Dysfunctional lactate metabolism in human alveolar type II cells from idiopathic pulmonary fibrosis lung explant tissue

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Danforth A. Newton ◽  
Robyn G. Lottes ◽  
Rita M. Ryan ◽  
Demetri D. Spyropoulos ◽  
John E. Baatz
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Initiation Site ◽  
Experimental Manipulation ◽  
Interstitial Lung Diseases ◽  
Alveolar Type ◽  
Type Ii ◽  
Lactate Metabolism ◽  
Human Patient ◽  
Lung Transplants

Abstract Background Idiopathic Pulmonary Fibrosis (IPF) is the most common and progressive form of the interstitial lung diseases, leading most patients to require lung transplants to survive. Despite the relatively well-defined role of the fibroblast in the progression of IPF, it is the alveolar type II epithelial cell (AEC2) that is now considered the initiation site of damage, driver of disease, and the most efficacious therapeutic target for long-term resolution. Based on our previous studies, we hypothesize that altered lactate metabolism in AEC2 plays a pivotal role in IPF development and progression, affecting key cellular and molecular interactions within the pulmonary microenvironment. Methods AEC2s isolated from human patient specimens of non-fibrotic and IPF lungs were used for metabolic measurements, lactate dehydrogenase (LDH) analyses and siRNA-mediated knockdown experiments. Results AEC2s isolated from human IPF lung explant tissues had lower rates of oxidative metabolism and were more glycolytic lactate-producing cells than were AEC2 from control, non-fibrotic lung explant tissues. Consistent with this shift in metabolism, patient-derived IPF AEC2s exhibited LDH tetramers that have higher ratios of LDHA:LDHB (i.e., favoring pyruvate to lactate conversion) than control AEC2s. Experimental manipulation of LDHA subunit expression in IPF AEC2s restored the bioenergetic profile characteristic of AEC2 from non-fibrotic lungs. Conclusions These results are consistent with the concept that altered lactate metabolism may be an underlying feature of AEC2 dysfunction in IPF and may be a novel and important target for therapeutic treatment.

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