A conserved pathway of transdifferentiation in murine Kupffer cells,European Journal of Immunology

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A conserved pathway of transdifferentiation in murine Kupffer cells
European Journal of Immunology ( IF 4.5 ) Pub Date : 2021-07-29 , DOI: 10.1002/eji.202049124
Xinyu Li ₁ , Nicole Hollingshead ₂ , Sarah Lampert ₂ , Camtu D Truong ₂ , Wanyu Li ₁ , Junqi Niu ₁ , Ian N Crispe _{2,

3} , Radika Soysa ₂

Affiliation

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.

中文翻译：

鼠库普弗细胞转分化的保守途径

在慢性肝损伤期间，大量长寿命的肝脏驻留巨噬细胞（称为库普弗细胞）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，导致它们转分化为沉积胶原蛋白的肌成纤维细胞。在其他组织中，与伤口相关的巨噬细胞更进一步，转分化为纤维细胞，自身分泌胶原蛋白。我们在两个实验模型中测试了库普弗细胞的这种特性：混合非实质细胞培养和精确切割的肝切片培养。使用 Emr1-Cre 转基因作为驱动程序和 RiboTag 转基因作为报告基因，我们发现库普弗细胞在这些情况下会发生转分化。随着时间的推移，它们失去了库普弗细胞特异性和巨噬细胞特异性基因的表达，以及控制它们表达的转录因子，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。这些效应在非实质细胞培养和肝组织切片培养之间高度保守，认为这种转分化是库普弗细胞的保守功能。我们得出结论，除了通过对星状细胞的作用支持纤维化外，库普弗细胞还通过转分化为纤维细胞参与肝纤维化。这些效应在非实质细胞培养和肝组织切片培养之间高度保守，认为这种转分化是库普弗细胞的保守功能。我们得出结论，除了通过对星状细胞的作用支持纤维化外，库普弗细胞还通过转分化为纤维细胞参与肝纤维化。这些效应在非实质细胞培养和肝组织切片培养之间高度保守，认为这种转分化是库普弗细胞的保守功能。我们得出结论，除了通过对星状细胞的作用支持纤维化外，库普弗细胞还通过转分化为纤维细胞参与肝纤维化。

更新日期：2021-10-06

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