Glucocorticoid regulates mesenchymal cell differentiation required for perinatal lung morphogenesis and function

Bridges, James P.; Sudha, Parvathi; Lipps, Dakota; Wagner, Andrew J.; Guo, Minzhe; Du, Yina; Brown, Kari; Filuta, Alyssa; Kitzmiller, Joseph A.; Stockman, Courtney A.; Rothenberg, Marc E.; Weirauch, Matthew T.; Jobe, Alan H.; Whitsett, Jeffrey A.; Xu, Yan

doi:10.1152/ajplung.00459.2019

Cited by 22 publications

(22 citation statements)

References 82 publications

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“…In bronchial tissue sections of asthma patients, the expression of several proproliferative proteins in the epithelium correlated with the dosage of therapeutic glucocorticoids [ 41 ]. During lung maturation the GR is the key regulator of mesenchymal cell differentiation [ 42 ]. Furthermore, it has been shown that glucocorticoids inhibit the proliferation of ASMC, through the activation of the GR [ 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

Bronchial thermoplasty in asthma: an exploratory histopathological evaluation in distinct asthma endotypes/phenotypes

et al. 2021

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Background Bronchial thermoplasty regulates structural abnormalities involved in airway narrowing in asthma. In the present study we aimed to investigate the effect of bronchial thermoplasty on histopathological bronchial structures in distinct asthma endotypes/phenotypes. Methods Endobronchial biopsies (n = 450) were collected from 30 patients with severe uncontrolled asthma before bronchial thermoplasty and after 3 sequential bronchial thermoplasties. Patients were classified based on blood eosinophils, atopy, allergy and smoke exposure. Tissue sections were assessed for histopathological parameters and expression of heat-shock proteins and glucocorticoid receptor. Proliferating cells were determined by Ki67-staining. Results In all patients, bronchial thermoplasty improved asthma control (p < 0.001), reduced airway smooth muscle (p = 0.014) and increased proliferative (Ki67 +) epithelial cells (p = 0.014). After bronchial thermoplasty, airway smooth muscle decreased predominantly in patients with T2 high asthma endotype. Epithelial cell proliferation was increased after bronchial thermoplasty in patients with low blood eosinophils (p = 0.016), patients with no allergy (p = 0.028) and patients without smoke exposure (p = 0.034). In all patients, bronchial thermoplasty increased the expression of glucocorticoid receptor in epithelial cells (p = 0.018) and subepithelial mesenchymal cells (p = 0.033) and the translocation of glucocorticoid receptor in the nucleus (p = 0.036). Furthermore, bronchial thermoplasty increased the expression of heat shock protein-70 (p = 0.002) and heat shock protein-90 (p = 0.001) in epithelial cells and decreased the expression of heat shock protein-70 (p = 0.009) and heat shock protein-90 (p = 0.002) in subepithelial mesenchymal cells. The effect of bronchial thermoplasty on the expression of heat shock proteins -70 and -90 was distinctive across different asthma endotypes/phenotypes. Conclusions Bronchial thermoplasty leads to a diminishment of airway smooth muscle, to epithelial cell regeneration, increased expression and activation of glucocorticoid receptor in the airways and increased expression of heat shock proteins in the epithelium. Histopathological effects appear to be distinct in different endotypes/phenotypes indicating that the beneficial effects of bronchial thermoplasty are achieved by diverse molecular targets associated with asthma endotypes/phenotypes.

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Section: Discussionmentioning

confidence: 99%

Bronchial thermoplasty in asthma: an exploratory histopathological evaluation in distinct asthma endotypes/phenotypes

et al. 2021

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“…Following FN1-KO extension, the number of human infrapatellar fat pad derived stem cells was increased, but this rise was negated by FN1 cells after implantation into ECM [23]. Likewise, recent ndings have found that the glucocorticoid receptor enhances the proliferative mesenchymal progenitor cell's acquisition of broblast matrix-derived signals such as Fn1 through and Wnt-1 and JAK-STAT, concerning their activity in the extracellular environment by other cells, and thus indirectly regulates a subset of those cells responsible for promoting tissue extracellular matrix gene expression, especially the cells [24]. Therefore in this study, we might be supposed that Fn1 is one of the major factors that enhance the reprogramming factors of FBs into iPSCs It's well known that in cell cycle control, especially mitosis, cyclin-dependent kinase 1 (CDK1) plays a key role.…”

Section: Discussionmentioning

confidence: 92%

Identification of Genes During the Reprogramming of Fibroblast using Bioinformatics Analysis

Wu¹,

Sai²,

Tang³

et al. 2021

Preprint

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Bioinformatics method was used to screen Human induced pluripotent stem cells reprogrammed by Human Fibroblasts (FBs). The reprogramming efficiency was explored by difference expressed genes (DEGs) before and after the expression of hiPSCs. Likewise, microarray datasets GSE34309, GSE43996, and GSE56805 datasets were downloaded from Gene Expression Omnibus (GEO) and GEO2R to screen the differentially expressed DEGs. Further, Gene Ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways were analyzed by David database. Likewise, to explore the correlation between DEGs, and the STRING database software was used to construct the protein-protein internet (PPI), and the Cytoscape_v3.7.2 Cytohubba plug-in was used to screen out the core genes. A total of 622 DEGs were identified, including 344 up regulated genes and 278 down-regulated genes. DEGs were mainly concentrated in the cell cycle and PI3K-Akt signaling pathway. Among the ten core genes screened, CDK1, IL6, EGFR, FN1, CDH1, SOX2, BRCA1, EZH2, CD44, and CCNB1 were most significant in the reprogramming of FBs into iPSCs. Regardless underline the differential of those gene expression profiles and regulatory network during FBs reprogramming could provide a theoretical basis for efficient reprogramming.

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“…89 Recent findings identified that glucocorticoid receptor expression in pulmonary fibroblasts modulates alveolar maturation. 9 Glucocorticoid enhanced the differentia-…”

Section: Signaling Pathways Specify Fibroblast Subpopulations and Control Fibroblast Functionmentioning

confidence: 99%

“…7 All four of these cell populations arrive at precisely the right time to provide both the scaffold and the paracrine signals the epithelium needs to proliferate and differentiate. The advent of single-cell RNA sequencing (scRNAseq) and the refinement of inducible mouse lineage-tracing systems have yielded a plethora of data on the interstitial lung fibroblast during alveolarization, [6][7][8][9][10][11][12] but individually analyzing these data can be overwhelming. In this review, we summarize the role of alveolar fibroblasts in alveolar septation and regeneration and incorporate them into context of how they are modified in and contribute to human lung diseases like BPD, IPF, and COPD.…”

Section: Introductionmentioning

confidence: 99%

Resident Interstitial Lung Fibroblasts and their Role in Alveolar Stem Cell Niche Development, Homeostasis, Injury, and Regeneration

Ushakumary

Riccetti

Perl

2021

Stem Cells Translational Medicine

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Developing, regenerating, and repairing a lung all require interstitial resident fibroblasts (iReFs) to direct the behavior of the epithelial stem cell niche. During lung development, distal lung fibroblasts, in the form of matrix-, myo-, and lipofibroblasts, form the extra cellular matrix (ECM), create tensile strength, and support distal epithelial differentiation, respectively. During de novo septation in a murine pneumonectomy lung regeneration model, developmental processes are reactivated within the iReFs, indicating progenitor function well into adulthood. In contrast to the regenerative activation of fibroblasts upon acute injury, chronic injury results in fibrotic activation. In murine lung fibrosis models, fibroblasts can pathologically differentiate into lineages beyond their normal commitment during homeostasis. In lung injury, recently defined alveolar niche cells support the expansion of alveolar epithelial progenitors to regenerate the epithelium. In human fibrotic lung diseases like bronchopulmonary dysplasia (BPD), idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD), dynamic changes in matrix-, myo-, lipofibroblasts, and alveolar niche cells suggest differential requirements for injury pathogenesis and repair. In this review, we summarize the role of alveolar fibroblasts and their activation stage in alveolar septation and regeneration and incorporate them into the context of human lung disease, discussing fibroblast activation stages and how they contribute to BPD, IPF, and COPD.

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Glucocorticoid regulates mesenchymal cell differentiation required for perinatal lung morphogenesis and function

Cited by 22 publications

References 82 publications

Bronchial thermoplasty in asthma: an exploratory histopathological evaluation in distinct asthma endotypes/phenotypes

Bronchial thermoplasty in asthma: an exploratory histopathological evaluation in distinct asthma endotypes/phenotypes

Identification of Genes During the Reprogramming of Fibroblast using Bioinformatics Analysis

Resident Interstitial Lung Fibroblasts and their Role in Alveolar Stem Cell Niche Development, Homeostasis, Injury, and Regeneration

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