Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, India.
Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India.
Life Sci. 2021 Dec 15;287:120119. doi: 10.1016/j.lfs.2021.120119. Epub 2021 Nov 4.
Hepatic fibrosis in injured liver is characterized by the activation of hepatic stellate cells (HSCs) from their quiescent state. Survivin (BIRC5) is one of the key genes that are upregulated during activation of HSCs but their role in HSC activation and fibrosis progression is unknown. Here, we have investigated the role of survivin protein in early fibrogenic activation of HSCs and fibrosis progression in chronic liver injury.
MATERIALS & METHODS: Primary quiescent HSCs were isolated from healthy mice liver through perfusion and cultured for fibrogenic activation. Survivin expression was suppressed by its pharmacological suppressant, YM155. We developed chronic liver injury induced fibrotic mice model through administrating repeated dose of CCl for 2 weeks and 4 weeks. Mice were pre-treated with YM155 a week before CCl administration till 2nd week of dosing and then discontinued. Hepatic parameters were characterized and underlying mechanisms were investigated.
Survivin expression gradually increased along with the expression of αSMA, collagen I activation maker in HSCs during their activation from quiescent state. Survivin suppression through YM155 downregulated αSMA, collagen I. Pre-treatment of YM155 in mice ceased the early activation of HSCs and onset of fibrosis in injured liver. However, discontinuation of YM155 initiated the activation of HSCs and fibrosis progression that shows survivin expression in HSCs is essential for their early activation and onset of liver fibrosis.
Survivin expression induces with activation of HSCs and drives onset of liver fibrosis in injured liver. Targeting survivin protein in activated HSCs could be a potential anti-fibrotic therapeutic approach in chronic liver injury.
损伤肝脏中的肝纤维化以静止状态的肝星状细胞（HSCs）的激活为特征。Survivin（BIRC5）是 HSCs 激活时上调的关键基因之一，但它们在 HSC 激活和纤维化进展中的作用尚不清楚。在这里，我们研究了 survivin 蛋白在 HSCs 早期纤维生成激活和慢性肝损伤纤维化进展中的作用。
通过灌注从健康小鼠肝脏中分离出静止的原代 HSCs，并进行纤维生成激活培养。通过其药理学抑制剂 YM155 抑制 survivin 表达。通过重复给予 CCl 2 周和 4 周，我们建立了慢性肝损伤诱导的纤维化小鼠模型。YM155 在 CCl 给药前一周开始预处理，直至第 2 周给药，并在第 2 周停药。对肝组织学参数进行了表征，并对潜在机制进行了研究。
在 HSCs 从静止状态激活过程中，survivin 表达逐渐增加，同时αSMA 和胶原 I 激活标志物也表达增加。通过 YM155 抑制 survivin 表达可下调αSMA 和胶原 I。在小鼠中预先给予 YM155 可阻止 HSCs 的早期激活和损伤肝脏中纤维化的发生。然而，YM155 的停药会引发 HSCs 的激活和纤维化进展，表明 HSCs 中的 survivin 表达对于其早期激活和肝纤维化的发生是必需的。
Survivin 表达伴随着 HSCs 的激活而诱导，并驱动损伤肝脏中的肝纤维化发生。针对激活的 HSCs 中的 survivin 蛋白可能是慢性肝损伤中一种有潜力的抗纤维化治疗方法。
