Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cancer Institute, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, China.
Parasit Vectors. 2023 Jun 6;16(1):184. doi: 10.1186/s13071-023-05791-4.
Schistosomiasis is a serious but neglected parasitic disease in humans that may lead to liver fibrosis and death. Activated hepatic stellate cells (HSCs) are the principal effectors that promote the accumulation of extracellular matrix (ECM) proteins during hepatic fibrosis. Aberrant microRNA-29 expression is involved in the development of fibrotic diseases. However, less is known about the role of miR-29 in Schistosoma japonicum (S. japonicum)-induced hepatic fibrosis.
The levels of microRNA-29a-3p (miR-29a-3p) and Roundabout homolog 1 (Robo1) were examined in liver tissues during S. japonicum infection. The possible involvement of the miR-29a-3p-Robo1 signaling pathway was determined. We used MIR29A conditional knock-in mice and mice injected with an miR-29a-3p agomir to investigate the role of miR-29a-3p in schistosomiasis-induced hepatic fibrosis. The functional contributions of miR-29a-3p-Robo1 signaling in liver fibrosis and HSC activation were investigated using primary mouse HSCs and the human HSC cell line LX-2.
MiR-29a-3p was downregulated in humans and mice with schistosome-induced fibrosis, and Robo1 was upregulated in liver tissues. The miR-29a-3p targeted Robo1 and negatively regulated its expression. Additionally, the expression level of miR-29a-3p in schistosomiasis patients was highly correlated with the portal vein and spleen thickness diameter, which represent the severity of fibrosis. Furthermore, we demonstrated that efficient and sustained elevation of miR-29a-3p reversed schistosome-induced hepatic fibrosis. Notably, we showed that miR-29a-3p targeted Robo1 in HSCs to prevent the activation of HSCs during infection.
Our results provide experimental and clinical evidence that the miR-29a-3p-Robo1 signaling pathway in HSCs plays an important role in the development of hepatic fibrosis. Therefore, our study highlights the potential of miR-29a-3p as a therapeutic intervention for schistosomiasis and other fibrotic diseases.
血吸虫病是一种严重但被忽视的人类寄生虫病，可导致肝纤维化和死亡。活化的肝星状细胞（HSCs）是在肝纤维化过程中促进细胞外基质（ECM）蛋白积累的主要效应细胞。异常的 microRNA-29 表达参与了纤维性疾病的发展。然而，关于 miR-29 在日本血吸虫（S. japonicum）诱导的肝纤维化中的作用知之甚少。
在日本血吸虫感染过程中检测了肝组织中 microRNA-29a-3p（miR-29a-3p）和 Roundabout 同源物 1（Robo1）的水平。确定了 miR-29a-3p-Robo1 信号通路的可能参与。我们使用 MIR29A 条件敲入小鼠和注射 miR-29a-3p 激动剂的小鼠来研究 miR-29a-3p 在日本血吸虫诱导的肝纤维化中的作用。使用原代小鼠 HSCs 和人 HSC 细胞系 LX-2 研究了 miR-29a-3p-Robo1 信号在肝纤维化和 HSC 活化中的功能贡献。
miR-29a-3p 在感染日本血吸虫的纤维化患者和小鼠中下调，而 Robo1 在肝组织中上调。miR-29a-3p 靶向 Robo1 并负调控其表达。此外，血吸虫病患者 miR-29a-3p 的表达水平与门静脉和脾脏厚度直径高度相关，这代表纤维化的严重程度。此外，我们证明有效的和持续的 miR-29a-3p 升高可逆转日本血吸虫感染引起的肝纤维化。值得注意的是，我们表明 miR-29a-3p 在 HSCs 中靶向 Robo1 以防止感染期间 HSCs 的激活。
我们的研究结果提供了实验和临床证据，表明 HSCs 中的 miR-29a-3p-Robo1 信号通路在肝纤维化的发展中起重要作用。因此，我们的研究强调了 miR-29a-3p 作为治疗血吸虫病和其他纤维化疾病的潜在治疗干预措施的潜力。
