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Abstract：
Abundant long-lived liver-resident macrophages, termed Kupffer cells, are activated during chronic liver injury. They secrete both pro-inflammatory and pro-fibrotic cytokines, which act on hepatic stellate cells causing their transdifferentiation into myofibroblasts that deposit collagen. In other tissues, wound-associated macrophages go further, and transdifferentiate into fibrocytes, secreting collagen themselves. We tested Kupffer cells for this property in two experimental models: mixed non-parenchymal cell culture, and precision-cut liver slice culture. Using the Emr1-Cre transgene as a driver and the RiboTag transgene as a reporter, we found that Kupffer cells undergo transdifferentiation under these circumstances. Over time, they lose the expression of both Kupffer cell-specific and macrophage-specific genes and the transcription factors that control their expression, and they begin to express multiple genes and proteins characteristic of either myofibroblasts or tissue fibroblasts. These effects were strongly conserved between non-parenchymal cell culture and liver tissue slice culture, arguing that such transdifferentiation is a conserved function of Kupffer cells. We conclude that in addition to supporting fibrosis through an action on stellate cells, Kupffer cells also participate in liver fibrosis through transdifferentiation into fibrocytes.
摘要：
丰富的长寿命肝脏驻留巨噬细胞，称为库普弗细胞，在慢性肝损伤期间被激活。它们分泌促炎和促纤维化细胞因子，作用于肝星状细胞，使其转分化为沉积胶原蛋白的肌成纤维细胞。在其他组织中，伤口相关的巨噬细胞走得更远，并转分化为纤维细胞，分泌胶原蛋白本身。我们在两个实验模型中测试了Kupffer细胞的这种特性：混合非实质细胞培养，和精确切割的肝切片培养。使用Emr1-Cre转基因作为驱动因子，使用RiboTag转基因作为报告因子，我们发现Kupffer细胞在这些情况下进行转分化。随着时间的推移,它们失去了Kupffer细胞特异性和巨噬细胞特异性基因的表达以及控制其表达的转录因子，它们开始表达肌成纤维细胞或组织成纤维细胞特有的多种基因和蛋白质。这些影响在非实质细胞培养和肝组织切片培养之间非常保守，认为这种转分化是Kupffer细胞的保守功能。我们得出的结论是，除了通过对星状细胞的作用来支持纤维化，枯否细胞还通过转分化为纤维细胞参与肝纤维化。
