Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Key Laboratory of Infection and Immunity, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
Stem Cell Res Ther. 2021 Oct 21;12(1):546. doi: 10.1186/s13287-021-02589-y.
Hepatic schistosomiasis, a chronic liver injury induced by long-term Schistosoma japonicum (S. japonicum) infection, is characterized by egg granulomas and fibrotic pathology. Hepatic progenitor cells (HPCs), which are nearly absent or quiescent in normal liver, play vital roles in chronic and severe liver injury. But their role in the progression of liver injury during infection remains unknown.
In this study, the hepatic egg granulomas, fibrosis and proliferation of HPCs were analyzed in the mice model of S. japonicum infection at different infectious stages. For validating the role of HPCs in hepatic injury, tumor necrosis factor-like-weak inducer of apoptosis (TWEAK) and TWEAK blocking antibody were used to manipulate the proliferation of HPCs in wild-type and IL-33 mice infected with S. japonicum.
We found that the proliferation of HPCs was accompanied by inflammatory granulomas and fibrosis formation. HPCs expansion promoted liver regeneration and inhibited inflammatory egg granulomas, as well as the deposition of fibrotic collagen. Interestingly, the expression of IL-33 was negatively associated with HPCs' expansion. There were no obvious differences of liver injury caused by infection between wild-type and IL-33 mice with HPCs' expansion. However, liver injury was more attenuated in IL-33 mice than wild-type mice when the proliferation of HPCs was inhibited by anti-TWEAK.
Our data uncovered a protective role of HPCs in hepatic schistosomiasis in an IL-33-dependent manner, which might provide a promising progenitor cell therapy for hepatic schistosomiasis.
由长期日本血吸虫（S. japonicum）感染引起的肝血吸虫病是一种慢性肝损伤，其特征为虫卵肉芽肿和纤维病理。肝前体细胞（HPCs）在正常肝脏中几乎不存在或处于静止状态，在慢性和严重肝损伤中发挥重要作用。但它们在感染过程中肝损伤进展中的作用尚不清楚。
在本研究中，我们在不同感染阶段的日本血吸虫感染小鼠模型中分析了肝虫卵肉芽肿、纤维化和 HPCs 的增殖。为了验证 HPCs 在肝损伤中的作用，我们使用肿瘤坏死因子样弱凋亡诱导剂（TWEAK）和 TWEAK 阻断抗体来操纵感染日本血吸虫的野生型和 IL-33 小鼠中 HPCs 的增殖。
我们发现 HPCs 的增殖伴随着炎症性肉芽肿和纤维化形成。HPCs 的扩增促进了肝再生，并抑制了炎症性虫卵肉芽肿和纤维胶原的沉积。有趣的是，IL-33 的表达与 HPCs 的扩增呈负相关。在 HPCs 扩增的野生型和 IL-33 小鼠中，感染引起的肝损伤没有明显差异。然而，当通过抗-TWEAK 抑制 HPCs 的增殖时，IL-33 小鼠的肝损伤比野生型小鼠更明显。
我们的数据揭示了 HPCs 在依赖于 IL-33 的肝血吸虫病中的保护作用，这可能为肝血吸虫病提供一种有前途的祖细胞治疗方法。
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