Enhanced Myofibroblastic Differentiation and Survival in Thy-1(−) Lung Fibroblasts

Sanders, Yan Y.; Kumbla, Pallavi A.; Hagood, James S.

doi:10.1165/rcmb.2006-0178oc

Cited by 126 publications

(132 citation statements)

References 45 publications

(56 reference statements)

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“…7 Heterogeneous surface expression of Thy-1 in fibroblasts results in the specialization of fibroblast, including Thy-1 (+) and Thy-1 (− ) subsets. Hagood et al 5,8,9 reported that lack of Thy-1 expression on lung fibroblasts contributed to IPF. Recently, it was found that epigenetic mechanisms, such as promoter hypermethylation and histone modification, play an important role in Thy-1 gene silencing in lung fibroblasts.…”

mentioning

confidence: 99%

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

Xing

Nie

et al. 2015

Laboratory Investigation

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Lipopolysaccharide (LPS)-induced proliferation of lung fibroblasts is closely correlated with loss of gene expression of thymocyte differentiation antigen-1 (Thy-1), accompanied with deacetylation of histones H3 and H4 at the Thy-1 gene promoter region; however, the mechanism remains enigmatic. We report here that LPS downregulates Thy-1 gene expression by activating histone deacetylases (HDACs) via Toll-like receptor 4 (TLR4) signaling. Treatment of primary cultured mouse lung fibroblasts with LPS resulted in significant upregulation of TLR4 and enhanced cell proliferation that was abolished by silencing TLR4 with lentivirus-delivered TLR4 shRNA. Interestingly, LPS increased the mRNA and protein levels of HDAC-4, -5, and -7, an effect that was abrogated by HDAC inhibitor trichostatin A (TSA) or TLR4-shRNA-lentivirus. Consistent with these findings, Ace-H3 and Ace-H4 were decreased by LPS that was prevented by TSA. Most importantly, chromosome immunoprecipitation (ChIP) analysis demonstrated that LPS decreased the association of Ace-H4 at the Thy-1 promoter region that was efficiently restored by pretreatment with TSA. Accordingly, LPS decreased the mRNA and protein levels of Thy-1 that was inhibited by TSA. Furthermore, silencing the Thy-1 gene by lentivirus-delivered Thy-1 shRNA could promote lung fibroblast proliferation, even in the absence of LPS. Conversely, overexpressing Thy-1 gene could inhibit lung fibroblast proliferation and reduce LPS-induced lung fibroblast proliferation. Our data suggest that LPS upregulates and activates HDACs through TLR4, resulting in deacetylation of histones H3 and H4 at the Thy-1 gene promoter that may contribute to Thy-1 gene silencing and lung fibroblast proliferation. Pulmonary fibrosis is characterized by aberrant proliferation and activation of lung fibroblasts. 1,2 The phenotypic transition of lung fibroblasts during the process of pulmonary fibrosis can be stimulated by various pathological conditions, including lipopolysaccharide (LPS), a component of bacteria membranes and an important player during the development of pulmonary fibrosis. 3,4 LPS-induced proliferation of lung fibroblast is associated with the silencing of thymocyte differentiation antigen-1 (Thy-1) and deacetylation of histones H3 and H4 at the Thy-1 gene promoter; 5,6 however, the mechanism by which LPS promotes the deacetylation of histones H3 and H4 leading to downregulation of Thy-1 gene expression is largely unknown.Thy-1 is a cell surface glycoprotein that is present in normal lung fibroblasts but absent from the fibroblastic foci of idiopathic pulmonary fibrosis (IPF). 7 Heterogeneous surface expression of Thy-1 in fibroblasts results in the specialization of fibroblast, including Thy-1 (+) and Thy-1 (− ) subsets. Hagood et al 5,8,9 reported that lack of Thy-1 expression on lung fibroblasts contributed to IPF. Recently, it was found that epigenetic mechanisms, such as promoter hypermethylation and histone modification, play an important role in Thy-1 gene silencing in lung fibroblasts. 6,7 Our...

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confidence: 99%

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

Xing

Nie

et al. 2015

Laboratory Investigation

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“…These Thy-1 (Ϫ) lung fibroblasts exhibit increased motility, contractility, and expression of myofibroblastic characteristics as compared with Thy-1 (ϩ) cells. [12][13][14][15][16] TGF-␤ bioavailability is regulated by complex factors, including agents that control activation, synthesis and processing, and deposition in the extracellular matrix (ECM). 17 Latent TGF-␤ binding proteins (LTBP-1, -2, -3, and -4) are a family of fibrillin-like molecules that contain multiple unique 8-cysteine repeats and multiple EGF-like domains.…”

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Latent Transforming Growth Factor-β-Binding Protein-4 Regulates Transforming Growth Factor-β1 Bioavailability for Activation by Fibrogenic Lung Fibroblasts in Response to Bleomycin

Zhou

Koli

Hagood

et al. 2009

The American Journal of Pathology

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“…To this end, E12.5-E13.5 MEFs were FACS-sorted into four phenotypically distinct subpopulations based on the surface expression of Thy1 (CD90) and Sca1 (stem cell antigen 1) markers. Previous studies demonstrated that Thy1 expression defines lipofibroblastic or myofibroblastic lineage, 26 while Sca1 is a marker specifying murine mesenchymal and epithelial progenitor cells. 27 Our microarray analyses confirmed that Sca1-single-positive cells (SP) express genes broadly involved in embryonic and tissue morphogenesis, thus indicating their immature origin (Supplemental Table 1), whereas Thy1/Sca1-doublenegative (DN) cells selectively express markers of myofibroblast-committed progenitors (Supplemental Table 2).…”

Section: Resultsmentioning

confidence: 99%

Two-factor reprogramming of somatic cells to pluripotent stem cells reveals partial functional redundancy of Sox2 and Klf4

et al. 2012

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Ectopic expression of defined sets of transcription factors in somatic cells enables them to adopt the qualities of pluripotency. Mouse embryonic fibroblasts (MEFs) are the classic target cell used to elucidate the core principles of nuclear reprogramming. However, their phenotypic and functional heterogeneity represents a major hurdle for mechanistic studies aimed at defining the molecular nature of cellular plasticity. We show that reducing the complexity of MEFs by flow cytometry allows the isolation of discrete cell subpopulations that can be efficiently reprogrammed to pluripotency with fewer genes. Using these FACS-sorted cells, we performed a systematic side-by-side analysis of the reprogramming efficiency with different two-and three-factor combinations of Oct4, Sox2 and Klf4. We show that introduction of exogenous Oct4 with either Sox2 or Klf4 does not directly convert MEFs to a pluripotent state. Instead, each combination of factors disrupts the normal cellular homeostasis and establishes transient states characterized by the concurrent expression of mixed lineage markers. These cells convert into induced pluripotent stem cells in a stochastic fashion. Our data suggest that there is a partial functional redundancy between Sox2 and Klf4 in the disruption of cellular homeostasis and activation of regulatory networks that define pluripotency. Reprogramming somatic cells into induced pluripotent stem (iPS) cells represents a valuable resource for the development of general and patient-specific therapies. The crucial issues facing the clinical translation of iPS technology are (i) choosing the most appropriate cell type for induction of pluripotency; (ii) improving the reprogramming efficiency; and (iii) gaining a mechanistic understanding of the reprogramming process. To date, multiple cell types have been used for iPS production, including embryonic and adult fibroblasts, adipocytes, cardiomyocytes, epithelial, vascular, hematopoietic and neuronal progenitors.

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Enhanced Myofibroblastic Differentiation and Survival in Thy-1(−) Lung Fibroblasts

Cited by 126 publications

References 45 publications

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

Latent Transforming Growth Factor-β-Binding Protein-4 Regulates Transforming Growth Factor-β1 Bioavailability for Activation by Fibrogenic Lung Fibroblasts in Response to Bleomycin

Two-factor reprogramming of somatic cells to pluripotent stem cells reveals partial functional redundancy of Sox2 and Klf4

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