Lymphedema is a chronic, progressive disease that causes pain as well as heavy economic burdens to patients. Reconstruction of the impaired lymphatic system is the key to treat lymphedema. Currently, there is no cure, but mesenchymal stromal cells show promising potential for lymphatic endothelial regeneration. Adipose-derived stromal cells (ADSCs) have been proved to support lymphangiogenesis both in vivo and in vitro. However, the mechanism in vascular endothelial growth factor C-induced (VEGF-C-induced) lymphatic endothelial transdifferentiation of ADSCs remains unknown. In this study, we show a novel link between the Wingless and int-1 (Wnt) pathway and the lymphatic endothelial differentiation process. We used LiCl to activate Wnt and DKK-1 to inhibit Wnt. Compared with the Wnt inhibition group and the control groups, the Wnt activation group produced more lymphatic endothelial cell (LEC)-related mRNA and proteins. Besides, Wnt-activated ADSCs formed longer tubes in two-dimensional culture and promoted the growth of lymphatic vessels in a three-dimensional transwell ADSC-LEC co-culture system. Our results demonstrated that activation of Wnt during the lymphatic endothelial transdifferentiation of ADSCs would enhance the efficacy of VEGF-C treatment. We anticipate our assay to expand our knowledge of Wnt in cell transdifferentiation and lay a foundation for future efforts to explore a novel and effective ADSC-based therapy for lymphedema.

中文翻译：

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Wnt 信号传导在体外调节脂肪来源的基质细胞的淋巴内皮转分化

淋巴水肿是一种慢性进行性疾病，会给患者带来疼痛和沉重的经济负担。重建受损的淋巴系统是治疗淋巴水肿的关键。目前，尚无治愈方法，但间充质基质细胞显示出用于淋巴管内皮再生的有希望的潜力。已证明脂肪来源的基质细胞 (ADSC)在体内和体外均支持淋巴管生成. 然而，ADSCs 的血管内皮生长因子 C 诱导（VEGF-C 诱导）淋巴管内皮转分化的机制仍然未知。在这项研究中，我们展示了 Wingless 和 int-1 (Wnt) 通路与淋巴管内皮分化过程之间的新联系。我们使用 LiCl 来激活 Wnt 和 DKK-1 来抑制 Wnt。与Wnt抑制组和对照组相比，Wnt激活组产生更多的淋巴管内皮细胞（LEC）相关的mRNA和蛋白。此外，Wnt 激活的 ADSCs 在二维培养中形成更长的管，并在三维 transwell ADSC-LEC 共培养系统中促进淋巴管的生长。我们的结果表明，在 ADSCs 的淋巴内皮转分化过程中激活 Wnt 将增强 VEGF-C 治疗的功效。