Department of Biochemistry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
Department of Health Management, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
Sci Rep. 2020 Nov 5;10(1):19105. doi: 10.1038/s41598-020-76095-1.
Accumulated evidence suggests that activated pancreatic stellate cells (PSCs) serve as the main source of the extracellular matrix proteins accumulated under the pathological conditions leading to pancreatic fibrosis in chronic pancreatitis (CP). However, little is known about the mechanisms of PSC activation. PSCs have morphologic and functional similarities to hepatic stellate cells, which are activated by hydrogen peroxide-inducible clone-5 (Hic-5), a TGF-β1-induced protein. In this study, we investigated whether Hic-5 activates PSCs, which promote pancreatic fibrosis development in CP. Hic-5-knockout and wild type mice were subjected to caerulein injection to induce CP. Hic-5 expression was strongly upregulated in activated PSCs from human CP tissue and from mouse pancreatic fibrosis in caerulein-induced CP. Hic-5 deficiency significantly attenuated mouse pancreatic fibrosis and PSC activation in the experimental murine CP model. Mechanistically, Hic-5 knock down significantly inhibited the TGF-β/Smad2 signaling pathway, resulting in reduced collagen production and α-smooth muscle actin expression in the activated PSCs. Taken together, we propose Hic-5 as a potential marker of activated PSCs and a novel therapeutic target in CP treatment.
有证据表明，在导致慢性胰腺炎（CP）胰腺纤维化的病理条件下，激活的胰腺星状细胞（PSCs）作为细胞外基质蛋白积聚的主要来源。然而，关于 PSC 激活的机制知之甚少。PSCs 在形态和功能上与肝星状细胞相似，后者被转化生长因子-β1（TGF-β1）诱导蛋白 1 （Hic-5）激活。在这项研究中，我们研究了 Hic-5 是否激活 PSCs，从而促进 CP 中胰腺纤维化的发展。用蛙皮素注射法使 Hic-5 敲除和野生型小鼠产生 CP。人 CP 组织和蛙皮素诱导的 CP 小鼠胰腺纤维化中活化的 PSCs 中 Hic-5 的表达明显上调。在实验性 CP 小鼠模型中，Hic-5 缺乏可显著减轻胰腺纤维化和 PSC 激活。从机制上讲，Hic-5 的敲低显著抑制了 TGF-β/Smad2 信号通路，导致活化的 PSCs 中胶原产生和 α-平滑肌肌动蛋白表达减少。总之，我们提出 Hic-5 作为活化的 PSCs 的潜在标志物和 CP 治疗的新的治疗靶点。
