Nojiri Shunsuke, Tsuchiya Atsunori, Natsui Kazuki, Takeuchi Suguru, Watanabe Takayuki, Kojima Yuichi, Watanabe Yusuke, Kamimura Hiroteru, Ogawa Masahiro, Motegi Satoko, Iwasawa Takahiro, Sato Takeki, Kumagai Masaru, Ishii Yui, Kitayama Tomomi, Li Yu-Tung, Ouchi Yuya, Shimbo Takashi, Takamura Masaaki, Tamai Katsuto, Terai Shuji
Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
Inflamm Regen. 2021 Sep 27;41(1):28. doi: 10.1186/s41232-021-00177-4.
The liver has a high regenerative ability and can induce spontaneous regression of fibrosis when early liver damage occurs; however, these abilities are lost when chronic liver damage results in decompensated cirrhosis. Cell therapies, such as mesenchymal stem cell (MSC) and macrophage therapies, have attracted attention as potential strategies for mitigating liver fibrosis. Here, we evaluated the therapeutic effects of HMGB1 peptide synthesized from box A of high mobility group box 1 protein. Liver damage and fibrosis were evaluated using a carbon tetrachloride (CCl)-induced cirrhosis mouse model. The effects of HMGB1 peptide against immune cells were evaluated by single-cell RNA-seq using liver tissues, and those against monocytes/macrophages were further evaluated by in vitro analyses. Administration of HMGB1 peptide did not elicit a rapid response within 36 h, but attenuated liver damage after 1 week and suppressed fibrosis after 2 weeks. Fibrosis regression developed over time, despite continuous liver damage, suggesting that administration of this peptide could induce fibrolysis. In vitro analyses could not confirm a direct effect of HMGB1 peptide against monocyte/macrophages. However, macrophages were the most affected immune cells in the liver, and the number of scar-associated macrophages (Trem2+Cd9+ cells) with anti-inflammatory markers increased in the liver following HMGB1 treatment, suggesting that indirect effects of monocytes/macrophages were important for therapeutic efficacy. Overall, we established a new concept for cell-free therapy using HMGB1 peptide for cirrhosis through the induction of anti-inflammatory macrophages.
肝脏具有很高的再生能力，在早期肝损伤发生时能够诱导纤维化的自发消退；然而，当慢性肝损伤导致失代偿性肝硬化时，这些能力就会丧失。细胞疗法，如间充质干细胞（MSC）和巨噬细胞疗法，作为减轻肝纤维化的潜在策略已引起关注。在此，我们评估了由高迁移率族蛋白盒1（HMGB1）的A盒合成的HMGB1肽的治疗效果。使用四氯化碳（CCl）诱导的肝硬化小鼠模型评估肝损伤和纤维化情况。通过对肝组织进行单细胞RNA测序评估HMGB1肽对免疫细胞的影响，并通过体外分析进一步评估其对单核细胞/巨噬细胞的影响。给予HMGB1肽在36小时内未引起快速反应，但1周后减轻了肝损伤，2周后抑制了纤维化。尽管肝损伤持续存在，但纤维化消退仍随时间发展，这表明给予该肽可诱导纤维溶解。体外分析未能证实HMGB1肽对单核细胞/巨噬细胞有直接作用。然而，巨噬细胞是肝脏中受影响最大的免疫细胞，HMGB1治疗后肝脏中具有抗炎标记的瘢痕相关巨噬细胞（Trem2+Cd9+细胞）数量增加，这表明单核细胞/巨噬细胞的间接作用对治疗效果很重要。总体而言，我们通过诱导抗炎巨噬细胞建立了一种使用HMGB1肽治疗肝硬化的无细胞治疗新概念。
