Alteration in the transcriptome of lung resident fibroblast upon genetic knockdown of Wilms' tumor1 transcription factor

Pulmonary fibrosis (PF) is associated with many chronic lung diseases including Systemic sclerosis (SSc), Idiopathic Pulmonary Fibrosis (IPF) and Cystic Fibrosis (CF) which are characterized by the progressive accumulation of stromal cells and formation of scar tissue. Pulmonary fibrosis is a dysregulated response to alveolar injury which causes a progressive decline in lung function and refractory to current pharmacological therapies. Airway and alveolar epithelial cells and stromal cells contribute to pulmonary fibrosis but the cell-specific pathways and gene networks that are responsible for the pathophysiology are unknown. Recent published reports from our lab demonstrated the aberrant activation of Wilms' tumor1 (WT1) transcription factor in lung resident fibroblast and myofibroblast in IPF lung biopsies and the mouse model of transforming growth factor-α (TGFα) and bleomycin induced fibrosis. In this study, we sought to determine the role of WT1 in transcriptome changes in lung resident fibroblast during pulmonary fibrosis. Our results showed that WT1 regulates the transcriptional changes that are required for the fibroblast activation processes such fibroproliferation, myofibroblast transformation and extracellular matrix deposition during pulmonary fibrosis. Finally, this study demonstrates that WT1 is a critical regulator of fibroblast activation in IPF and hence serve as a target for therapeutic intervention.

肺纤维化（Pulmonary fibrosis, PF）与多种慢性肺部疾病相关，包括系统性硬化症（Systemic sclerosis, SSc）、特发性肺纤维化（Idiopathic Pulmonary Fibrosis, IPF）及囊性纤维化（Cystic Fibrosis, CF），此类疾病以基质细胞进行性积聚及瘢痕组织形成为特征。肺纤维化是肺泡损伤后的失调性应答反应，可导致肺功能进行性下降，且现有药物治疗难以奏效。气道上皮细胞与肺泡上皮细胞及基质细胞均参与肺纤维化的发生发展，但介导其病理生理过程的细胞特异性通路与基因网络仍未明确。本课题组近期发表的研究显示，在特发性肺纤维化患者的肺活检标本及转化生长因子-α（transforming growth factor-α, TGFα）联合博莱霉素诱导的纤维化小鼠模型中，肺驻留成纤维细胞与肌成纤维细胞内的Wilms瘤1（Wilms' tumor1, WT1）转录因子存在异常激活。本研究旨在明确WT1在肺纤维化进程中对肺驻留成纤维细胞转录组变化的调控作用。研究结果表明，在肺纤维化进程中，WT1可调控成纤维细胞活化所需的转录改变，包括成纤维增殖、肌成纤维细胞转化及细胞外基质沉积。本研究最终证实，WT1是特发性肺纤维化中成纤维细胞活化的关键调控因子，有望成为治疗干预的潜在靶点。