克罗恩病(CD)和溃疡性结肠炎(UC)是胃肠道的慢性炎症性疾病。慢性炎症是导致肠纤维化的主要因素,导致复发性狭窄,尤其是CD患者。目前,纤维化的分子机制尚不清楚.ZNF281是一种锌指转录调节因子,已被表征为上皮间质转化(EMT)诱导转录因子,表明它参与了多能性的调节,stemness,和癌症。这项研究的目的是在体内和体外研究ZNF281在肠纤维发生中的作用。在通过给予葡聚糖硫酸钠(DSS)的两个或三个周期诱导的患有慢性结肠炎的C57BL/6J小鼠中体内研究了肠纤维化。在人结肠成纤维细胞系CCD-18Co中体外研究了ZNF281对肠道纤维化的贡献,由促纤维化细胞因子TGFβ1激活。通过siRNA转染下调ZNF281,并进行RNA测序以鉴定通过ZNF281在活化的结肠成纤维细胞中由TGFβ1调节的基因。结果显示ZNF281在体内鼠纤维化结肠以及由TGFβ1激活的体外人结肠成纤维细胞中显著增加。此外,在TGFβ1处理的成纤维细胞中ZNF281的废除影响了属于与成纤维细胞活化和分化为肌成纤维细胞相关的特定途径的基因的表达。我们证明ZNF281是通过转录控制细胞外基质(ECM)组成,在纤维化刺激下结肠成纤维细胞活化和肌成纤维细胞分化的关键调节因子。重塑,和细胞收缩,强调在肠道纤维化的发生和发展中的新作用。
Crohn\'s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract. Chronic inflammation is the main factor leading to intestinal fibrosis, resulting in recurrent stenosis, especially in CD patients. Currently, the underlying molecular mechanisms of fibrosis are still unclear.
ZNF281 is a zinc-finger transcriptional regulator that has been characterized as an epithelial-to-mesenchymal transition (EMT)-inducing transcription factor, suggesting its involvement in the regulation of pluripotency, stemness, and cancer. The aim of this study is to investigate in vivo and in vitro the role of
ZNF281 in intestinal fibrogenesis. Intestinal fibrosis was studied in vivo in C57BL/6J mice with chronic colitis induced by two or three cycles of administration of dextran sulfate sodium (DSS). The contribution of
ZNF281 to gut fibrosis was studied in vitro in the human colon fibroblast cell line CCD-18Co, activated by the pro-fibrotic cytokine TGFβ1. ZNF281 was downregulated by siRNA transfection, and RNA-sequencing was performed to identify genes regulated by TGFβ1 in activated colon fibroblasts via
ZNF281. Results showed a marked increase of ZNF281 in in vivo murine fibrotic colon as well as in in vitro human colon fibroblasts activated by TGFβ1. Moreover, abrogation of
ZNF281 in TGFβ1-treated fibroblasts affected the expression of genes belonging to specific pathways linked to fibroblast activation and differentiation into myofibroblasts. We demonstrated that ZNF281 is a key regulator of colon fibroblast activation and myofibroblast differentiation upon fibrotic stimuli by transcriptionally controlling extracellular matrix (ECM) composition, remodeling, and cell contraction, highlighting a new role in the onset and progression of gut fibrosis.