Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice
Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice
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DOI：
10.1182/blood-2016-06-721571
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发表时间：
2017-01-26
期刊：
影响因子：
20.3
通讯作者：
Babitt, Jodie L.
中科院分区：
文献类型：
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作者：
Canali, Susanna;Zumbrennen-Bullough, Kimberly B.;Babitt, Jodie L.
肝细胞中的骨形态发生蛋白6(Bmp6)信号是铁激素海普西丁的中心转录调节因子，它控制全身铁平衡。铁水平如何调节海普西丁的产生尚不清楚，但铁对肝脏Bmp6表达的局部诱导被认为具有关键作用。为了确定负责海普西丁和铁稳态调节的Bmp6的细胞来源，我们在不同的肝细胞群中建立了组织特异性消融Bmp6的小鼠，并评估了它们的铁表型。通过使用Cre报告基因小鼠、基因组DNA聚合酶链式反应和从分离的肝细胞群中定量检测Bmp6信使RNA的表达来评估Cre介导的重组的效率和特异性。免疫荧光显微镜观察BMP共受体血凝素的定位。对Bmp6条件性基因敲除小鼠的分析表明，肝内皮细胞(ECs)表达Bmp6，而常驻肝巨噬细胞(Kupffer细胞)和肝细胞不表达Bmp6。内皮细胞中Bmp6的缺失概括了Bmp6基因敲除小鼠的血色素沉着表型，而肝细胞和巨噬细胞Bmp6条件性基因敲除小鼠没有表现出铁的表型。血凝素定位于肝细胞窦状膜上，紧邻产生Bmp6的肝窦内皮细胞。综上所述，这些数据表明，内皮细胞是肝脏中BMP6的主要来源，并支持ECBMP6对肝细胞血凝素具有旁分泌作用的模型，以调节肝素转录和维持全身铁平衡。
Bone morphogenetic protein 6 (BMP6) signaling in hepatocytes is a central transcriptional regulator of the iron hormone hepcidin that controls systemic iron balance. How iron levels are sensed to regulate hepcidin production is not known, but local induction of liver BMP6 expression by iron is proposed to have a critical role. To identify the cellular source of BMP6 responsible for hepcidin and iron homeostasis regulation, we generated mice with tissue-specific ablation ofBmp6in different liver cell populations and evaluated their iron phenotype. Efficiency and specificity of Cre-mediated recombination was assessed by using Cre-reporter mice, polymerase chain reaction of genomic DNA, and quantitation of Bmp6 messenger RNA expression from isolated liver cell populations. Localization of the BMP co-receptor hemojuvelin was visualized by immunofluorescence microscopy. Analysis of the Bmp6 conditional knockout mice revealed that liver endothelial cells (ECs) expressed Bmp6, whereas resident liver macrophages (Kupffer cells) and hepatocytes did not. Loss of Bmp6 in ECs recapitulated the hemochromatosis phenotype of global Bmp6 knockout mice, whereas hepatocyte and macrophage Bmp6 conditional knockout mice exhibited no iron phenotype. Hemojuvelin was localized on the hepatocyte sinusoidalmembrane immediately adjacent to Bmp6-producing sinusoidal ECs. Together, these data demonstrate that ECs are the predominantsource ofBMP6in the liver andsupport amodel inwhichECBMP6 has paracrine actionson hepatocytehemojuvelin to regulate hepcidin transcription and maintain systemic iron homeostasis.