Single-Nucleus Chromatin Accessibility Identifies a Critical Role for TWIST1 in IPF Myofibroblast Activity
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE214085 | GEO | 2023/05/04
REPOSITORIES: GEO
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Project description:Single-Nucleus Chromatin Accessibility Identifies a Critical Role for TWIST1 in IPF Myofibroblast Activity
| PRJNA883741 | ENA
Project description:Pericryptal myofibroblasts in the colon and rectum play an important role in regulating the normal colorectal stem cell niche and facilitating tumour progression. Myofibroblasts have previously mostly been distinguished from normal fibroblasts only by the expression of α smooth muscle actin (αSMA). We now identify AOC3, a surface monoamine oxidase, as a new marker of myofibroblasts by showing that it is the target protein of the myofibroblast reacting monoclonal antibody (mAb), PR2D3. The normal and tumour tissue distribution and the cell line reactivity of AOC3 match that expected for myofibroblasts. We have shown that the surface expression of AOC3 is sensitive to digestion by trypsin and collagenase and that anti-AOC3 antibodies can be used for FACS sorting of myofibroblasts obtained by non-enzymatic procedures. Whole genome microarray mRNA expression profiles of myofibroblasts and skin fibroblasts revealed four additional genes that are significantly expressed differentially between these two cell types; NKX2-3 and LRRC17 are expressed in myofibroblasts and SHOX2 and TBX5 in skin fibroblasts. Transforming Growth Factor β (TGFβ) substantially down-regulated AOC3 expression in myofibroblasts but not in skin fibroblasts, in which it dramatically increased the expression of αSMA. A knockdown of NKX2-3 in myofibroblasts caused a decrease of myofibroblast-related gene expression and an increased expression of the fibroblast associated gene, SHOX2, suggesting that NKX2-3 is a key mediator for maintaining myofibroblast characteristics. Our results show that colorectal myofibroblasts, as defined by the expression of AOC3, NKX2-3 and other markers, are a distinctly different cell type from TGFβ activated fibroblasts. colorectal myofibroblast specific markers and expression profiles were sought by comparing four primary myofibroblast cultures to a panel of four dermal and foreskin fibroblast cell lines Four primary myofibroblast cultures established from adult human colon compared to four skin fibroblast cell lines to identify intestinal myofibroblast specific markers
2016-04-06 | E-GEOD-77474 | biostudies-arrayexpress
Project description:Idiopathic pulmonary fibrosis (IPF), a chronic progressive lung disease of unknown etiology, is characterized by the expansion of myofibroblasts and abnormal deposition of extracellular matrix in the lung parenchyma. To elucidate the molecular mechanisms that lead to IPF, we analyzed myofibroblasts established from patients with IPF by oligonucleotide microarrays. Gene expression profiles revealed a novel pathophysiologic function of myofibroblasts as a generator of reactive oxygen species, and a self-defense mechanism against oxidative stress of their own generating. Experiment Overall Design: We isolated two myofibroblast cell culture from patients with idiopathic pulmonary fibrosis. Embryonic pulmonary fibroblast was used for the reference.
2008-06-15 | E-GEOD-6804 | biostudies-arrayexpress
Project description:Pericryptal myofibroblasts in the colon and rectum play an important role in regulating the normal colorectal stem cell niche and facilitating tumour progression. Myofibroblasts have previously mostly been distinguished from normal fibroblasts only by the expression of α smooth muscle actin (αSMA). We now identify AOC3, a surface monoamine oxidase, as a new marker of myofibroblasts by showing that it is the target protein of the myofibroblast reacting monoclonal antibody (mAb), PR2D3. The normal and tumour tissue distribution and the cell line reactivity of AOC3 match that expected for myofibroblasts. We have shown that the surface expression of AOC3 is sensitive to digestion by trypsin and collagenase and that anti-AOC3 antibodies can be used for FACS sorting of myofibroblasts obtained by non-enzymatic procedures. Whole genome microarray mRNA expression profiles of myofibroblasts and skin fibroblasts revealed four additional genes that are significantly expressed differentially between these two cell types; NKX2-3 and LRRC17 are expressed in myofibroblasts and SHOX2 and TBX5 in skin fibroblasts. Transforming Growth Factor β (TGFβ) substantially down-regulated AOC3 expression in myofibroblasts but not in skin fibroblasts, in which it dramatically increased the expression of αSMA. A knockdown of NKX2-3 in myofibroblasts caused a decrease of myofibroblast-related gene expression and an increased expression of the fibroblast associated gene, SHOX2, suggesting that NKX2-3 is a key mediator for maintaining myofibroblast characteristics. Our results show that colorectal myofibroblasts, as defined by the expression of AOC3, NKX2-3 and other markers, are a distinctly different cell type from TGFβ activated fibroblasts. colorectal myofibroblast specific markers and expression profiles were sought by comparing four primary myofibroblast cultures to a panel of four dermal and foreskin fibroblast cell lines
2016-04-06 | GSE77474 | GEO
Project description:As a group, fibroproliferative disorders of the lung, liver, kidney, heart, vasculature and integument are common, progressive and refractory to therapy. They can emerge following toxic insults, but are frequently idiopathic. Their enigmatic propensity to resist therapy and progress to organ failure has focused attention on the myofibroblast – the primary effector of the fibroproliferative response. A central unanswered question is whether these myofibroblasts have acquired a distinct pathological phenotype - or whether they are normal myofibroblasts with a pathological phenotype that depends upon residing in a sea of pro-fibrotic cytokines and an abnormal extracellular matrix. Using a systems approach to study this question in a prototype fibrotic disease, Idiopathic Pulmonary Fibrosis (IPF); here we show organized changes in the gene expression pathway of primary lung myofibroblasts that persist for up to 9 sub-cultivations in vitro. When comparing IPF and control myofibroblasts in a 3-dimensional type I collagen matrix, more genes differed at the level of ribosome recruitment than at the level of transcript abundance, indicating pathological translational control as a major characteristic of IPF myofibroblasts. To determine the effect of matrix state on translational control, myofibroblasts were permitted to contract the matrix. Ribosome recruitment in control myofibroblasts was relatively stable. In contrast, IPF cells manifested large alterations in the ribosome recruitment pattern. Pathological studies suggest an epithelial origin for IPF myofibroblasts through the epithelial to mesenchymal transition (EMT). In accord with this, we found systems-level indications for TGF?b -driven EMT as one source of IPF myofibroblasts. Keywords: cell type comparison Comparison of lung myofibroblasts from patients with Idiopatic Pulmonary Fibrosis (IPF, 6 donors) to control (6 donors) in contractile and non-contractile matrices using both total and polyribosomal RNA
2008-11-20 | E-GEOD-11196 | biostudies-arrayexpress
Project description:Idiopathic pulmonary fibrosis (IPF), a chronic progressive lung disease of unknown etiology, is characterized by the expansion of myofibroblasts and abnormal deposition of extracellular matrix in the lung parenchyma. To elucidate the molecular mechanisms that lead to IPF, we analyzed myofibroblasts established from patients with IPF by oligonucleotide microarrays. Gene expression profiles revealed a novel pathophysiologic function of myofibroblasts as a generator of reactive oxygen species, and a self-defense mechanism against oxidative stress of their own generating. Keywords: cell type comparison, disease state analysis
2008-01-17 | GSE6804 | GEO
Project description:Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell-type in terms of their origins and functional effects in vivo. Methods: Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen inducible Cre for cellular lineage tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Results: Lineage tracing with 4 additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin+ myofibroblasts reduces collagen production and scar formation after myocardial infarction. Periostin-traced myofibroblasts also revert back to a less activated state upon injury resolution. Conclusions: Our results define the myofibroblast as a periostin-expressing cell-type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21+ tissue-resident fibroblasts. Fluidigm C1 whole genome transcriptome analysis of lineage mapped cardiac myofibroblasts
2016-06-14 | E-GEOD-83337 | biostudies-arrayexpress
Project description:After skin injury fibroblasts migrate into the wound and transform into contractile extracellular matrix-producing myofibroblasts to promote skin repair. Persistent activation of myofibroblasts can cause excessive fibrotic reactions, but the underlying mechanisms are not fully understood. We used SMA-GFP transgenic mice to study myofibroblast recruitment and activation in skin wounds. Myofibroblasts were initially recruited to wounds three days post injury reached a maximum after seven days and subsequently declined. Expression profiling showed that 1749 genes were differentially expressed in sorted myofibroblasts from wounds seven days post injury. GO-Term analysis associated most of these genes with the extracellular region and cell periphery including upregulated genes encoding for ECM proteins, integrins and focal adhesion proteins and a specific set of growth factors, cytokines and chemokines promoting the healing response. In contrast, cell adhesion molecules involved in cell-cell interaction were downregulated. Novel genes not yet known to be expressed in myofibroblast were found. Hence, this first characterization of a myofibroblast specific expression network at the peak of granulation tissue formation in situ provides important insights into myofibroblast activation in skin wounds and identifies novel target genes to control excessive ECM deposition during fibrotic reactions.
2017-12-30 | GSE95786 | GEO
Project description:Keloids are characterized by abnormal wound healing with excessive accumulation of extracellular matrix. Myofibroblasts are the primary contributor to extracellular matrix secretion, playing an essential role in the wound healing process. However, the differences between myofibroblasts involved in keloid formation and normal wound healing remain unclear. To identify the specific characteristics of keloid myofibroblasts, we initially assessed the expression levels of well-established myofibroblast markers, α-smooth muscle actin (α-SMA) and transgelin (TAGLN), in scar and keloid tissues (n = 63 and 51, respectively). The objective was to evaluate the enrichment of myofibroblasts in these tissues. Although myofibroblasts were present in significant quantities in keloids and immature scars, they were absent in mature scars. Next, we conducted RNA sequencing using myofibroblast-rich areas from keloids and immature scars to investigate the difference in RNA expression profiles among myofibroblasts. Comparison of the results with publicly available RNA-sequencing datasets revealed that 112 genes were significantly upregulated and 108 genes were downregulated in keloid samples compared with immature scar samples. Among them, KN motif and ankyrin repeat domains 4 (KANK4) was identified as a specifically upregulated gene in keloids. Immunohistochemical analysis showed that KANK4 protein was expressed in myofibroblasts in keloid tissues; however, it was not expressed in any myofibroblasts in immature scar tissues. There are two main isoforms of KANK4 transcripts, with short isoforms being dominantly expressed in keloid tissue. Overexpression of the short isoform of KANK4 enhanced cell mobility in keloid myofibroblasts. Our results suggest that the KANK4-mediated increase in myofibroblast mobility contributes to keloid pathogenesis.
2024-03-19 | GSE245660 | GEO