RUNX1 promotes alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS in rat via NF-κ B pathway

Research Square (Research Square), Год журнала: 2023, Номер unknown

Опубликована: Апрель 26, 2023

Abstract Background Previous studies have confirmed that acute respiratory distress syndrome (ARDS) is characterized by alveolar hypercoagulation and fibrinolytic inhibition. However, the underlying mechanism remains unclear. Runt-related transcription factor 1 (RUNX1) a expressed in various organs, including lung tissue, involved multiple pathophysiological processes such as inflammation. We hypothesized RUNX1 participates regulating pathogenesis of ARDS, but whether it inhibition Methods In vivo, we observed expression tissue lipopolysaccharide (LPS)-induced ARDS rats down-regulated gene to confirm its regulatory role vitro, measured levels LPS-stimulated epithelial cell type II (AEC II) down-and up-regulated AEC cells using lentiviral infection technology determine cells. Finally, effect on NF-κ B pathway explored RUNX1. Results was significantly increased LPS-induced rats. Alveolar were rats, shown expressions (TF) plasminogen activator inhibitor (PAI-1) tissue. Meanwhile, NF-κB signaling also activated. Conditional knockdown inhibited downregulated TF PAI-1 pulmonary rat ARDS. found increased, with being Up-regulation further boosted PAI-1, activation well. Down-regulation gene, however, dramatically suppressed activation, even when compared those stimulated LPS alone. Conclusions regulates fibrinolysis The may be associated NF-KB activation. expected new target for improving

Язык: Английский

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Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors

Research Square (Research Square), Год журнала: 2023, Номер unknown

Опубликована: Авг. 16, 2023

Abstract Long-term toxicities caused by cancer treatments have recently gained increasing recognition due to a steadily growing population of survivors. Radiotherapy (RT) is common treatment known unintentionally harm surrounding normal tissuesincluding the skin, hindering wound healing even years after treatment. Our study aimed elucidate underlying mechanisms these late-onset adverse effects RT. By comparing paired skin biopsies from previously irradiated (RT + ) and non-irradiated − sites in breast survivors who underwent RT ago, we discovered compromised capacity impaired fibroblast functions skin. employing ATAC-seq, identified altered chromatin landscapes fibroblasts, pinpointing THBS1 as crucial epigenetically primed repair-related gene. Further confirmation THBS1's significance during repair came single-cell RNA-sequencing spatial transcriptomic analysis human wounds. Remarkably, heightened sustained expression was observed fibroblasts both mouse radiation models, leading motility contractility. Encouragingly, our found that with anti-THBS1 antibodies promoted ex vivo closure These findings indicate dermal retain long-term memory recorded form epigenetic changes. Targeting this maladaptive shows promise for mitigating RT, offering potential solutions improve quality life

Язык: Английский

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Lung injury epigenetically primes mesenchyme for amplified activation upon re-injury

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Март 4, 2022

Abstract The lungs have a remarkable capacity to repair. However, repetitive injury can lead progressive fibrosis and end-stage organ failure. Whether tissue-resident mesenchymal cell populations retain epigenetic memory of prior injuries that contribute this pathological process is unknown. Here we used genetic lineage labeling approach mark the lung mesenchyme injury, then performed multi-modal analyses on isolated during initiation, progression resolution fibrotic response. Our results demonstrate transcriptional plasticity fibrogenic activation de-activation. Despite plasticity, also find retains specific traits (memory) activation, resulting in amplified induction program upon re-injury. We identify Runx1 as critical driver both memory. Comparison fresh cultured demonstrates spontaneously activated standard culture conditions, previously masking these roles Runx1. Genetic pharmacological targeting dampens tissue models, confirming its functional importance. Finally, publicly available scRNAseq data reveal selective expression subpopulations emerge mouse human tissue. Collectively, our findings implicate initiation together prime responses repeated injury.

Язык: Английский

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Genomic, transcriptomic and proteomic depiction of iPSC-derived smooth muscle cells as emerging cellular models for arterial diseases

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Май 1, 2022

Abstract Background Vascular smooth muscle cells (VSMCs) plasticity is a central mechanism in cardiovascular health and disease. We aimed at providing deep cellular phenotyping, epigenomic proteomic depiction of SMCs derived from induced pluripotent stem (iPSCs) evaluating their potential as models the context complex genetic arterial diseases. Methods differentiated 3 human iPSC lines using either RepSox (R-SMCs) or PDGF-BB TGF-β (TP-SMCs), during second half 24-days-long protocol. In addition to assays, we performed RNA-Seq assay for transposase accessible chromatin (ATAC)-Seq 6 time-points differentiation. The extracellular matrix content (matrisome) generated by iPSCs was analyzed mass spectrometry. Results Both differentiation protocols with positive expression SMC markers. TP-SMCs exhibited greater capacity proliferation, migration lower calcium release response contractile stimuli compared R-SMCs. data showed that genes involved function arteries were highly expressed R-SMCs primary SMCs. Matrisome analyses supported an overexpression proteins wound repair higher secretion basal membrane constituents Open regions significantly enriched variants associated coronary artery disease blood pressure, while only peripheral Conclusions Our study portrayed two presenting complementary phenotypes high relevance plasticity. combination genome-editing tools, our supports use these regulatory mechanisms risk loci several Graphical

Язык: Английский

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