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.

淋巴管与血管一起在体液循环和免疫细胞募集中发挥重要作用。出生后淋巴管生成通常通过发芽从预先存在的淋巴管发生，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的关键信号和细胞类型，如人囊性淋巴管瘤，鲜为人知。在这里，我们发现渗入皮下植入海绵的小鼠真皮成纤维细胞响应 PDGFRβ 信号表达 VEGF-D 和 Sushi、Von Willebrand 因子 A、EGF 和含有 1 的 pentraxin 结构域（SVEP1）。体外，Pdgfrb敲除 (β-KO) 成纤维细胞降低了 VEGF-D 和 SVEP1 的表达并过度产生双调蛋白。这三个因素的失调与在 β-KO 小鼠中观察到的淋巴管的囊状和不均匀分布有关。同样，在人类囊性淋巴管瘤中，这是一种顽固性疾病，主要发生在儿童时期，囊性淋巴管周围的成纤维细胞高度表达双调蛋白。此外，成纤维细胞来源的双调节蛋白可以诱导淋巴管内皮细胞中双调节蛋白的表达。双调蛋白的双重来源激活了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，