George Whipple Lab for Cancer Research, Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Hepatology. 2013 Apr;57(4):1550-63. doi: 10.1002/hep.26135.
Transplantation of bone marrow mesenchymal stem cells (BM-MSCs) has been considered as an alternative therapy, replacing liver transplantation in clinical trials, to treat liver cirrhosis, an irreversible disease that may eventually lead to liver cancer development. However, low survival rate of the BM-MSCs leading to unsatisfactory efficacy remains a major concern. Gender differences have been suggested in BM-MSCs therapeutic application, but the effect of the androgen receptor (AR), a key factor in male sexual phenotype, in this application is not clear. Using two liver cirrhosis mouse models induced by CCl4 or thioacetamide, we showed that targeting AR in the BM-MSCs improved their self-renewal and migration potentials and increased paracrine effects to exert anti-inflammatory and anti-fibrotic actions to enhance liver repair. Mechanism dissection studies suggested that knocking out AR in BM-MSCs led to improved self-renewal and migration by alteration of the signaling of epidermal growth factor receptor and matrix metalloproteinase 9 and resulted in suppression of infiltrating macrophages and hepatic stellate cell activation through modulation of interleukin (IL)1R/IL1Ra signaling. Therapeutic approaches using either AR/small interfering RNA or the AR degradation enhancer, ASC-J9, to target AR in BM-MSCs all led to increased efficacy for liver repair.
Targeting AR, a key factor in male sexual phenotype, in BM-MSCs improves transplantation therapeutic efficacy for treating liver fibrosis.
骨髓间充质干细胞（BM-MSCs）的移植已被视为一种替代疗法，在临床试验中替代肝移植，以治疗肝硬化，这是一种不可逆转的疾病，最终可能导致肝癌的发展。然而，BM-MSCs 的低存活率导致疗效不佳仍是一个主要关注点。性别差异已被认为在 BM-MSCs 的治疗应用中存在，但雄激素受体（AR）的作用，即男性性表型的关键因素，在这种应用中的作用尚不清楚。使用 CCl4 或硫代乙酰胺诱导的两种肝硬化小鼠模型，我们表明靶向 BM-MSCs 中的 AR 可提高其自我更新和迁移潜力，并增加旁分泌作用，发挥抗炎和抗纤维化作用，增强肝脏修复。机制剖析研究表明，通过改变表皮生长因子受体和基质金属蛋白酶 9 的信号，敲除 BM-MSCs 中的 AR 可导致自我更新和迁移的改善，并通过调节白细胞介素（IL）1R/IL1Ra 信号抑制浸润巨噬细胞和肝星状细胞的激活。使用 AR/小干扰 RNA 或 AR 降解增强剂 ASC-J9 靶向 BM-MSCs 中的 AR 的治疗方法均能提高肝脏修复的疗效。
靶向 BM-MSCs 中的 AR，即男性性表型的关键因素，可提高移植治疗肝纤维化的疗效。
