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Dysregulation of Amphiregulin stimulates the pathogenesis of cystic lymphangioma [Medical Sciences]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-05-11 , DOI: 10.1073/pnas.2019580118
Naofumi Yoshida, Seiji Yamamoto, Takeru Hamashima, Noriko Okuno, Naruho Okita, Shinjiro Horikawa, Masao Hayashi, Thanh Chung Dang, Quang Linh Nguyen, Koichi Nishiyama, Teruhiko Makino, Yoko Ishii, Kei Tomihara, Tadamichi Shimizu, Masabumi Shibuya, Makoto Noguchi, Masakiyo Sasahara

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 PDGFRβ signal. In vitro, Pdgfrb knockout (β-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 β-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, fibroblast-derived 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.



中文翻译:

两性调节蛋白的失调刺激了囊性淋巴管瘤的发病机理[医学]

淋巴管与血管一起在体液循环和免疫细胞募集中起重要作用。产后淋巴管生成通常发生在发芽的淋巴管中,这是由淋巴管生成因子(如血管内皮生长因子C(VEGF-C))诱导的。然而,刺激病理性淋巴管生成的关键信号和细胞类型,例如人囊性淋巴管瘤,鲜为人知。在这里,我们发现,渗透到皮下植入的海绵中的小鼠真皮成纤维细胞对PDGFRβ信号表达VEGF-D和寿司,Von Willebrand因子A型,EGF和含有1(SVEP1)的五环素域。体外,Pdgfrb敲除(β-KO)成纤维细胞的VEGF-D和SVEP1的表达降低,而双调蛋白的产量过高。这三个因素的失调与在β-KO小鼠中观察到的淋巴管的囊样样和不均匀分布有关。同样,在人性囊性淋巴管瘤(这是一种难治的疾病,多发于儿童)中,囊性淋巴管周围的成纤维细胞高表达双调蛋白。此外,成纤维细胞衍生的双调蛋白可诱导双调蛋白在淋巴管内皮细胞中的表达。双调蛋白的双重来源激活了在淋巴管内皮细胞上表达的EGFR。这种恶化级联诱导淋巴管内皮细胞增殖,形成囊性淋巴管瘤。最终,

更新日期:2021-05-03
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