Dysregulation of Amphiregulin stimulates the pathogenesis of cystic lymphangioma
Dysregulation of Amphiregulin stimulates the pathogenesis of cystic lymphangioma
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DOI：
10.1073/pnas.2019580118
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发表时间：
2021-05-11
影响因子：
11.1
通讯作者：
Sasahara, Masakiyo
中科院分区：
文献类型：
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作者：
Yoshida, Naofumi;Yamamoto, Seiji;Sasahara, Masakiyo
与血管一样，淋巴管在体液循环和免疫细胞招募中发挥着重要作用。出生后淋巴管生成通常是由预先存在的淋巴管通过发芽发生的，这是由血管内皮生长因子 C (VEGF-C) 等淋巴管生成因子诱导的。然而，刺激病理性淋巴管生成（例如人类囊性淋巴管瘤）的关键信号和细胞类型却鲜为人知。在这里，我们发现，浸润到皮下植入海绵的小鼠真皮成纤维细胞响应 PDGFR β 信号而表达 VEGF-D 和 sushi、Von Willebrand 因子 A 型、EGF 和五聚蛋白结构域 1 (SVEP1)。在体外，Pdgfrb 敲除（β-KO）成纤维细胞的 VEGF-D 和 SVEP1 表达降低，并过量产生双调蛋白。这三个因素的失调与在 beta-KO 小鼠中观察到的淋巴管囊肿样和不均匀分布有关。同样，人类囊性淋巴管瘤是一种疑难杂症，多发生在儿童时期，囊性淋巴管周围的成纤维细胞高表达双调蛋白。此外，成纤维细胞来源的双调蛋白可以诱导淋巴内皮细胞中双调蛋白的表达。双调蛋白的双重来源激活了淋巴内皮细胞上表达的 EGFR。这种恶化级联诱导淋巴内皮细胞增殖形成囊性淋巴管瘤。最终，淋巴管周围的成纤维细胞和淋巴管内皮细胞本身产生的过量双调蛋白导致了囊性淋巴管瘤的发病机制，并且将成为囊性淋巴管瘤的一个令人着迷的治疗靶点。
Along with blood vessels, lymphatic vessels play an important role in the circulation of body fluid and recruitment of immune cells. Postnatal lymphangiogenesis commonly occurs from preexisting lymphatic vessels by sprouting, which is induced by lymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C). However, the key signals and cell types that stimulate pathological lymphangiogenesis, such as human cystic lymphangioma, are less well known. Here, we found that mouse dermal fibroblasts that infiltrate to sponges subcutaneously implanted express VEGF-D and sushi, Von Willebrand factor type A, EGF, and pentraxin domain containing 1 (SVEP1) in response to PDGFR beta signal. In vitro, Pdgfrb knockout (beta-KO) fibroblasts had reduced expression of VEGF-D and SVEP1 and overproduced Amphiregulin. Dysregulation of these three factors was involved in the cyst-like and uneven distribution of lymphatic vessels observed in the beta-KO mice. Similarly, in human cystic lymphangioma, which is one of the intractable diseases and mostly occurs in childhood, fibroblasts surrounding cystic lymphatics highly expressed Amphiregulin. Moreover, fibroblastderived Amphiregulin could induce the expression of Amphiregulin in lymphatic endothelial cells. The dual source of Amphiregulin activated EGFR expressed on the lymphatic endothelial cells. This exacerbation cascade induced proliferation of lymphatic endothelial cells to form cystic lymphangioma. Ultimately, excessive Amphiregulin produced by fibroblasts surrounding lymphatics and by lymphatic endothelial cells per se results in pathogenesis of cystic lymphangioma and will be a fascinating therapeutic target of cystic lymphangioma.