Wnt Signaling Regulates the Lymphatic Endothelial Transdifferentiation of Adipose-Derived Stromal Cells In Vitro

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.