Hematopoietic Transcription Factor RUNX1 is Essential for Promoting Macrophage–Myofibroblast Transition in Non‐Small‐Cell Lung Carcinoma

Advanced Science, Год журнала: 2023, Номер 11(1)

Опубликована: Ноя. 15, 2023

Abstract Macrophage‐myofibroblast transition (MMT) is a newly discovered pathway for mass production of pro‐tumoral cancer‐associated fibroblasts (CAFs) in non‐small cell lung carcinoma (NSCLC) TGF‐β1/Smad3 dependent manner. Better understanding its regulatory signaling tumor microenvironment (TME) may identify druggable target the development precision medicine. Here, by dissecting transcriptome dynamics tumor‐associated macrophage at single‐cell resolution, crucial role hematopoietic transcription factor Runx1 MMT formation revealed. Surprisingly, integrative bioinformatic analysis uncovers as key regulator downstream MMT‐specific signaling. Stromal level positively correlates with MMT‐derived CAF abundance and mortality NSCLC patients. Mechanistically, macrophage‐specific promotes genes related to signatures cells genomic level. Importantly, genetic deletion systemic pharmacological inhibition TGF‐β1/Smad3/Runx1 effectively prevent MMT‐driven vitro vivo, representing potential therapeutic clinical NSCLC.

Язык: Английский

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Mesenchymal stem cells-derived exosomes carrying microRNA-30b confer protection against pulmonary fibrosis by downregulating Runx1 via Spred2

Molecular Genetics and Genomics, Год журнала: 2024, Номер 299(1)

Опубликована: Март 13, 2024

Язык: Английский

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Neonatal hyperoxia induces activated pulmonary cellular states and sex-dependent transcriptomic changes in a model of experimental bronchopulmonary dysplasia

AJP Lung Cellular and Molecular Physiology, Год журнала: 2022, Номер 324(2), С. L123 - L140

Опубликована: Дек. 20, 2022

Hyperoxia disrupts lung development in mice and causes bronchopulmonary dysplasia (BPD) neonates. To investigate sex-dependent molecular cellular programming involved hyperoxia, we surveyed the mouse using single cell RNA sequencing (scRNA-seq), validated our findings human neonatal cells vitro. Hyperoxia-induced inflammation alveolar type (AT) 2 gave rise to damage-associated transient progenitors (DATPs). It also induced a new subpopulation of AT1 with reduced expression growth factors normally secreted by cells, but increased mitochondrial gene expression. Female epithelial had less EMT pulmonary fibrosis signaling hyperoxia. In endothelium, expansion Car4+ EC (Cap2) was seen hyperoxia along an emergent Cap2 repressed VEGF signaling. This regenerative response females exposed Mesenchymal inflammatory signatures distal interstitial fibroblast subcluster characterized lipid biosynthesis transcriptomic signature resembling myofibroblasts. fibroblasts vitro resembled scRNA-seq data. These suggest that exposure programs distinct sex-specific stem progenitor reparative responses underpin remodeling BPD.

Язык: Английский

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Genomic, Transcriptomic, and Proteomic Depiction of Induced Pluripotent Stem Cells–Derived Smooth Muscle Cells As Emerging Cellular Models for Arterial Diseases

Hypertension, Год журнала: 2023, Номер 80(4), С. 740 - 753

Опубликована: Янв. 19, 2023

Vascular smooth muscle cells (SMCs) plasticity is a central mechanism in cardiovascular health and disease. We aimed at providing cellular phenotyping, epigenomic proteomic depiction of SMCs derived from induced pluripotent stem evaluating their potential as models the context complex diseases.Human cell lines were differentiated using RepSox (R-SMCs) or PDGF-BB (platelet-derived growth factor-BB) TGF-β (transforming factor beta; TP-SMCs), during 24-day long protocol. RNA-Seq assay for transposase accessible chromatin-Seq performed 6 time points differentiation, mass spectrometry was used to quantify proteins.Both differentiation protocols generated with positive expression SMC markers. TP-SMCs exhibited greater proliferation capacity, migration lower calcium release response contractile stimuli, compared R-SMCs. Genes involved function arteries highly expressed R-SMCs primary SMCs. coronary artery transcriptomic profiles similar, characterized by high genes blood pressure regulation identified FOXF1 HAND1 key drivers specific program. Extracellular matrix content contained more proteins wound repair higher secretion basal membrane constituents Open chromatin regions significantly enriched variants associated disease.Both cell-derived present complementary phenotypes relevance plasticity. These study functional genetic risk loci main arterial diseases.

Язык: Английский

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RUNX1 promotes liver fibrosis progression through regulating TGF‐β signalling

International Journal of Experimental Pathology, Год журнала: 2023, Номер 104(4), С. 188 - 198

Опубликована: Апрель 17, 2023

Abstract Liver fibrosis is caused by chronic liver injury. There are limited treatments for it, and the pathogenesis unclear. Therefore, there an urgent need to explore of fibrosis, try identify new potential therapeutic targets. For this study we used carbon tetrachloride abdominal injection induced animal model in mice. Primary hepatic stellate cell isolation was performed a density‐gradient separation method, followed immunofluorescence stain analyses. Signal pathway analysis dual‐luciferase reporter assay western blotting. Our results showed that RUNX1 upregulated cirrhotic tissues compared with normal tissues. Besides, overexpression more severe lesions than control group under CCl 4 ‐induced conditions. Moreover, α‐SMA expression significantly higher group. Interestingly, found could promote activation TGF‐β/Smads assay. Thus demonstrated be considered as regulator activating signalling. Based on this, concluded may developed target treatment future. In addition, also provides insight about aetiology fibrosis.

Язык: Английский

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Fibroblast-Specific Depletion of Human Antigen R Alleviates Myocardial Fibrosis Induced by Cardiac Stress

JACC Basic to Translational Science, Год журнала: 2024, Номер 9(6), С. 754 - 770

Опубликована: Июнь 1, 2024

Cardiac fibrosis can be mitigated by limiting fibroblast-to-myofibroblast differentiation and proliferation. Human antigen R (HuR) modulates messenger RNA stability expression of multiple genes. However, the direct role cardiac myofibroblast HuR is unknown. Myofibroblast-specific deletion limited preserved functions in pressure overload injury. Knockdown transforming growth factor-β1–treated fibroblasts suppressed abrogated cyclins D1 A2, suggesting a potential mechanism which promotes Overall, these data suggest that inhibition could therapeutic approach to limit fibrosis.

Язык: Английский

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Altered AP-1, RUNX, and EGR chromatin dynamics drive fibrotic lung disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 28, 2024

Pulmonary fibrosis, including systemic sclerosis-associated interstitial lung disease (SSc-ILD), involves myofibroblasts and SPP1

Язык: Английский

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Deciphering the immune landscape dominated by cancer-associated fibroblasts to investigate their potential in indicating prognosis and guiding therapeutic regimens in high grade serous ovarian carcinoma

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Сен. 2, 2022

Limited immunotherapeutic effect in high-grade serous ovarian carcinoma (HGSOC) propels exploration of the mechanics behind this resistance, which may be partly elucidated by investigating characters cancer-associated fibroblasts (CAFs), a significant population HGSOC involved shaping tumor immune microenvironment. Herein, leveraging gene expression data samples from The Cancer Genome Atlas and Gene Expression Omnibus datasets, we suggested that CAFs detrimentally affected outcomes patients. Subsequently, performed weighted co-expression network analysis (WGCNA) to identify CAFs-related module screened out seven hub genes module, all were positively correlated with infiltration immunosuppressive macrophages. As one genes, fibrillin 1 (FBN1) its relevance CD206 further verified immunohistochemistry staining samples. Meanwhile, extracted well CAF signatures construct CAFscore. capacity CAFscore as an independent prognostic factor was validated Cox regression analyses, components signals microenvironment also investigated. Under evaluation CAFscore, patients relatively high had worse outcomes, activated mesenchymal signaling pathways, checkpoint blockade (ICB) resistance signatures, consistent fact non-responders anti-PD-1 treatment cohorts tended have higher Besides, possibility guide selection sensitive chemotherapeutic agents explored. In conclusion, individualized assessment could uncover extent stroma activation immunosuppression inform therapeutic strategies improve benefit therapies.

Язык: Английский

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Vitamin D3 analogue calcipotriol inhibits the profibrotic effects of transforming growth factor- β1 on pancreatic stellate cells

European Journal of Pharmacology, Год журнала: 2023, Номер 957, С. 176000 - 176000

Опубликована: Авг. 19, 2023

To evaluate the inhibitory effect of vitamin D3 analogue calcipotriol (Cal) on fibrosis pancreatic stellate cells (PSCs) induced by TGF-β1 and rationality Cal use in alcoholic chronic pancreatitis (ACP). Double-labeling immunofluorescence was used for identification VDR+PSCs pancreas healthy controls (HC) ACP patients. Van Gieson staining examination collagen fibers. RT-qPCR Western Blot determining mRNAs proteins VDR, COL1A1 or vitro PSCs. ELISA LC-MS/MS detection serum 25(OH)D3. The PSC line (RP-2 cell) determination proteomic alterations plus versus to examine VDR gene knockdown. Enhanced expression detected RP-2 stimulated with alcohol (ALC) alone PSCs HC. increased were positively correlated levels areas deposition ACP. overexpressed ALC-treated while 25(OH)D3 level significantly decreased Through a VDR-dependent mechanism, antagonized 16 profibrotic TGF-β1-induced that included 7 extracellular matrix components, 2 cytoskeletal proteins, fibrosis-associated factors (RUNX1 TRAF2), TIMP-1, CCN1, integrin α11, an adhesion scaffold protein (TGFB1i1) enzyme mediating fibrogenesis (ENPP1). This study suggests administration may be potential antifibrotic strategy via inhibiting TGF-β1-mediated action during development

Язык: Английский

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RUNX1-Regulated Signaling Pathways in Ovarian Cancer

Biomedicines, Год журнала: 2023, Номер 11(9), С. 2357 - 2357

Опубликована: Авг. 23, 2023

Ovarian cancer is the leading cause of gynecological death worldwide, and its poor prognosis high mortality seriously affect life ovarian patients. Runt-related transcription factor 1 (RUNX1) has been widely studied in hematological diseases plays an important role occurrence development diseases. In recent years, studies have reported roles RUNX1 solid tumors, including significantly increased expression cancer. cancer, dysregulation signaling pathway implicated tumor progression, metastasis, response to therapy. At same time, decreased can improve sensitivity clinical chemotherapy provide theoretical support for subsequent diagnosis treatment target providing options patients with However, remains unclear. Therefore, this article reviews relationship between as well closely regulated pathways, some inspiration future research on other

Язык: Английский

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