Endothelial cell clonal expansion in the development of cerebral cavernous malformations
Endothelial cell clonal expansion in the development of cerebral cavernous malformations
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DOI：
10.1038/s41467-019-10707-x
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发表时间：
2019-06-24
影响因子：
16.6
通讯作者：
Dejana, Elisabetta
中科院分区：
文献类型：
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作者：
Malinyerno, Matteo;Maderna, Claudio;Dejana, Elisabetta
脑海绵状血管瘤 (CCM) 是一种神经血管家族性或散发性疾病，其特征是毛细血管-静脉海绵状血管瘤，是由于三个 CCM 基因中任何一个基因的功能丧失突变所致。家族性 CCM 遵循与肿瘤抑制基因相似的二次打击机制，而在散发性海绵状血管瘤中，只有一小部分内皮细胞显示出突变的 CCM 基因。我们报道，在小鼠模型和人类患者中，病变内衬的内皮细胞与周围的内皮细胞具有不同的特征，因为它们表达间充质/干细胞标记物。在这里，我们发现海绵状血管瘤起源于少数表达间充质/干细胞标记物的 Ccm3 缺失内皮细胞的克隆扩增。然后这些细胞吸引周围的野生型内皮细胞，诱导它们表达间充质/干细胞标记物并促进海绵状瘤的生长。 Ccm3 缺失细胞的这些特征让人想起负责肿瘤生长的肿瘤起始细胞。我们的数据支持 CCM 具有良性肿瘤特征的概念。
Cerebral cavernous malformation (CCM) is a neurovascular familial or sporadic disease that is characterised by capillary-venous cavernomas, and is due to loss-of-function mutations to any one of three CCM genes. Familial CCM follows a two-hit mechanism similar to that of tumour suppressor genes, while in sporadic cavernomas only a small fraction of endothelial cells shows mutated CCM genes. We reported that in mouse models and in human patients, endothelial cells lining the lesions have different features from the surrounding endothelium, as they express mesenchymal/stem-cell markers. Here we show that cavernomas originate from clonal expansion of few Ccm3-null endothelial cells that express mesenchymal/stem-cell markers. These cells then attract surrounding wild-type endothelial cells, inducing them to express mesenchymal/stem-cell markers and to contribute to cavernoma growth. These characteristics of Ccm3-null cells are reminiscent of the tumour-initiating cells that are responsible for tumour growth. Our data support the concept that CCM has benign tumour characteristics.