Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China; State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China.
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China.
J Hepatol. 2017 Oct;67(4):770-779. doi: 10.1016/j.jhep.2017.05.022. Epub 2017 Jul 26.
BACKGROUND & AIMS: Macrophages play vital roles in chronic liver injury, and have been tested as a tool for cytotherapy in liver fibrosis. However, macrophages possess ontogenic and functional heterogeneities. Some subsets are pro-fibrotic, whereas others are anti-fibrotic. This study aimed to clarify which macrophage subset is efficient for cytotherapy in liver fibrosis and to elucidate the underlying mechanisms.
Liver fibrosis was induced in mice by carbon tetrachloride injection or bile duct ligation. Bone-marrow-derived macrophages (BMDMs) were polarized into M0, M1, or M2 macrophages, respectively. BMDMs were infused into mice through the tail vein at different stages of fibrogenesis. Fibrosis progression, hepatic cell populations, and related molecular changes were evaluated.
Both M0 and M1 BMDMs significantly ameliorated liver fibrosis, but M1 exhibited stronger therapeutic effects than M0. M2 macrophages were not effective on liver fibrosis. M1 macrophages reduced the number and activation of hepatic stellate cells (HSCs), which could be attributed at least partly to increased HSC apoptosis. M1 macrophages enhanced the recruitment of endogenous macrophages into fibrotic liver, which displayed the phenotype of Ly6C restorative macrophages and produced matrix metalloproteinases (MMPs) and hepatic growth factor (HGF) to enhance collagen degradation and hepatocyte proliferation, respectively. M1 macrophages also increased the number of total and activated natural killer (NK) cells in the fibrotic liver, which released TNF-related apoptosis-inducing ligand (TRAIL), inducing HSC apoptosis.
M1 macrophages, which modulate the immune microenvironment to recruit and modify the activation of endogenous macrophages and NK cells, are effective for cytotherapy in experimental liver fibrosis. Lay summary: M1 Bone marrow-derived macrophages (BMDMs) exhibit a stronger therapeutic effect by modulating the hepatic microenvironment to recruit and modify the activation of endogenous macrophages and natural killer (NK) cells, which likely lead to hepatic stellate cells (HSCs) apoptosis and hampered fibrogenesis.
巨噬细胞在慢性肝损伤中发挥着重要作用，并已被尝试作为肝纤维化细胞治疗的工具。然而，巨噬细胞具有不同的起源和功能异质性。一些亚群具有促纤维化作用，而另一些则具有抗纤维化作用。本研究旨在阐明哪种巨噬细胞亚群对肝纤维化的细胞治疗有效，并阐明其潜在机制。
通过四氯化碳注射或胆管结扎诱导小鼠肝纤维化。将骨髓来源的巨噬细胞（BMDM）分别极化为 M0、M1 或 M2 巨噬细胞。在纤维化发生的不同阶段，通过尾静脉将 BMDM 输注到小鼠体内。评估纤维化进展、肝细胞群体和相关分子变化。
M0 和 M1 BMDM 均显著改善肝纤维化，但 M1 的治疗效果更强。M2 巨噬细胞对肝纤维化无效。M1 巨噬细胞减少了肝星状细胞（HSC）的数量和激活，这至少部分归因于 HSC 凋亡的增加。M1 巨噬细胞增强了内源性巨噬细胞向纤维性肝脏的募集，这些巨噬细胞表现出 Ly6C 修复性巨噬细胞的表型，并产生基质金属蛋白酶（MMPs）和肝细胞生长因子（HGF），分别增强胶原降解和肝细胞增殖。M1 巨噬细胞还增加了纤维性肝脏中总 NK 细胞和激活 NK 细胞的数量，NK 细胞释放 TNF 相关凋亡诱导配体（TRAIL），诱导 HSC 凋亡。
M1 巨噬细胞通过调节免疫微环境招募和改变内源性巨噬细胞和 NK 细胞的激活，对实验性肝纤维化的细胞治疗有效。
M1 骨髓来源的巨噬细胞（BMDM）通过调节肝脏微环境招募和改变内源性巨噬细胞和自然杀伤（NK）细胞的激活，发挥更强的治疗效果，这可能导致肝星状细胞（HSC）凋亡和阻止纤维化发生。
