Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, No 639, Zhizaoju Road, Huangpu District, Shanghai, 200011, China.
Department of Pathology, Affiliated Obstetrics and Gynecology Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu province, China.
Stem Cell Res Ther. 2019 Jan 11;10(1):16. doi: 10.1186/s13287-018-1122-8.
Liver fibrosis is a key phase that will progress to further injuries such as liver cirrhosis or carcinoma. This study aimed to investigate whether transplantation of bone marrow mesenchymal stromal cells (BM-MSCs) can attenuate liver fibrosis in mice and the underlying mechanisms based on the regulation of macrophage subtypes.
A liver fibrosis model was induced by intraperitoneal (i.p.) injection of CCl4 twice per week for 70 days, and BM-MSCs were intravenously transplanted twice on the 60th and 70th days. Immunohistology and gene expression of liver fibrosis and macrophage subtypes were analyzed. Mouse RAW264.7 cells and JS1 cells (hepatic stellate cell strain) were also used to explore the underlying mechanisms of the effects of BM-MSCs on liver fibrosis.
After transplantation of BM-MSCs, F4/80CD206-activated M2 macrophages and matrix metalloproteinase 13 (MMP 13) expression were significantly increased while F4/80iNOS-activated M1 macrophages were inhibited in liver tissue. Gene expression of IL-10 was elevated while IL12b, IFN-γ, TNF-α, and IL-6 gene expression were decreased. ΤGF-β1 and collagen-1 secretions were reduced while caspase-3 was increased in JS1 cells treated with BM-MSC-conditioned media. BM-MSCs effectively suppressed the expression of α-SMA, Sirius red, and collagen-1 in the liver, which are positively correlated with fibrosis and induced by CCl4 injection.
Taken together, we have provided the first demonstration that BM-MSC transplantation can promote the activation of M2 macrophages expressing MMP13 and inhibition of M1 macrophages to further inhibit hepatic stellate cells (HSCs), which play synergistic roles in attenuating liver fibrosis.
肝纤维化是向肝硬化或肝癌等进一步损伤发展的关键阶段。本研究旨在探讨骨髓间充质干细胞（BM-MSCs）移植是否可以通过调节巨噬细胞亚型来减轻小鼠的肝纤维化，并探讨其潜在机制。
通过每周两次腹腔（i.p.）注射 CCl4 诱导肝纤维化模型，共 70 天，在第 60 天和第 70 天两次静脉注射 BM-MSCs。分析肝纤维化和巨噬细胞亚型的免疫组织化学和基因表达。还使用小鼠 RAW264.7 细胞和 JS1 细胞（肝星状细胞株）来探讨 BM-MSCs 对肝纤维化影响的潜在机制。
BM-MSCs 移植后，F4/80CD206 激活的 M2 巨噬细胞和基质金属蛋白酶 13（MMP 13）表达显著增加，而 F4/80iNOS 激活的 M1 巨噬细胞受到抑制。IL-10 基因表达上调，而 IL12b、IFN-γ、TNF-α 和 IL-6 基因表达下调。BM-MSC 条件培养基处理的 JS1 细胞中 TGF-β1 和胶原-1 的分泌减少，而 caspase-3 增加。BM-MSCs 有效抑制了 CCl4 注射诱导的α-SMA、茜素红和胶原-1在肝脏中的表达，这些表达与纤维化呈正相关。
综上所述，我们首次证明 BM-MSC 移植可以促进表达 MMP13 的 M2 巨噬细胞的激活和 M1 巨噬细胞的抑制，从而进一步抑制肝星状细胞（HSCs），这在减轻肝纤维化中发挥协同作用。
