Abstract Body: As part of the circulatory system, the lymphatic vasculature is essential for maintaining fluid homeostasis, immune surveillance, and fat uptake from the intestinal tract. Lymphatic vessel insufficiency or dysfunction is associated with various pathologic conditions including lymphedema, and most recent myocardial infarction, atherosclerosis, and neurological disorders. Despite the importance of lymphatic function in health and disease, the molecular mechanisms controlling the development and function of lymphatic vessels remain poorly understood.
The chemokine receptor CXCR4 primarily signals via its ligand CXCL12, inducing intracellular signaling cascades critical for cell proliferation, migration, and survival. Although numerous studies have highlighted its crucial roles in regulating angiogenesis and tissue regeneration, knowledge about its role in lymphangiogenesis is limited. We recently published that mouse embryos with lymphatic endothelial cells (LECs) specific deficiency of CXCR4 exhibited severe edema with impaired lymphatic vasculature. Similarly, CXCL12 mutant embryos showed comparable lymphatic vascular defects during development, strongly suggesting that CXCL12/CXCR4 is essential for lymphatic development. Intriguingly, we demonstrated that CXCL12 is primarily expressed by Schwann cells (SCs) surrounding peripheral nerves in embryo skins. Furthermore, CXCL12/CXCR4 is required for VEGFC mediated VEGFR3/PI3K/AKT activities to regulate lymphangiogenesis. These exciting findings demonstrated that SC-derived CXCL12 interacts with LEC-derived CXCR4 to guide lymphatic vessel development and function. (Do et al., Development, in press). We further elucidated the molecular mechanisms by which CXCL12/CXCR4 regulate lymphatic development. We found CXCL12/CXCR4 induces YAP/TAZ activities and upregulates Myc expression to control LEC proliferation and migration. we will determine the functional role of CXCL12/CXCR4 in pathological lymphangiogenesis and its therapeutic potentials using a surgical induced tail lymphedema model.
This work will uncover previously unknown chemokine mediated signaling from nerves that regulates lymphatic development and function. Furthermore, it will provide mechanistic insights into the pathogenesis of lymphedema and propose novel therapeutic approaches for treating lymphedema and other lymphatic-related diseases.