| Gaps in the Field of Lymphatic Research | 2026–27 Update | 5 4. Evaluation of Lymphatic Anatomy • How is the nervous system involved in lymphatic communication, and in which ways does nervous system innervation impact lymphatic capacity, flow, and function? • Need to map the entire human lymphatic system in health and in disease. • What are the main lymphatic anatomy variants of the upper extremity, lower extremities, and the body in general? • How does the presence or absence of any anatomic variant potentially contribute to the incidence of lymphedema or other lymphatic diseases? 5. Understanding Cellular Behavior • Explore role of lymphatic circulating tumor cells (CTCs) from various metastatic tumors to clarify their parallel, hematogenous and lymphagenous dissemination, and role of various subpopulations of lymphatic CTCs (e.g., cancer stem cells) in metastasis progression. Also, uncover the pathways and interactions between blood and lymphatic circulating cells, exosomes, and other lymph components. • Use AI to develop models of cell behavior in a complex lymph microenvironment. 6. Need for Accurate and Widely Available Animal Models A major gap and need in studying lymphatics is the availability of animal models that recapitulate the diverse biology and heterogeneity of human lymphatics (especially organ specific lymphatics in health and disease). For example: aspects of mouse lymphatic physiology do not apply to humans; i.e., visceral and thoracic collecting lymphatics do not pump, and mice are not exposed to chronic gravitational loads. No animal models exist for the human condition of lipedema. 7. Lymphatic Endothelial Cell (LEC) Specification • Identify genes controlling the earliest steps of lymphatic endothelial cell (LEC) specification. • Development of in vitro systems to derive LECs from human embryonic stem cells. • Determine the plasticity of LEC phenotype and its regulation by metabolic factors. • We need to identify relevant molecules and cells with which LECs communicate in vivo. • How do mutant endothelial cells affect normal endothelial cells? • How do complex lymphatic anomaly-causing genetic mutations affect different LEC populations and how do mutant LECs affect normal LECs? 8. The Role of the Lymphatic System in Different Organs of the Human Body in Health and in Disease How and why do lymphatics of certain organs become dysfunctional, causing disease? Examples of organ specific gaps in lymphatic knowledge: • Lymphatics of the eye -> Understanding patho- physiology of glaucoma, retinal and optic nerve diseases, and corneal transplant rejection. • Lymphatics of the liver (a key organ of lymph production) -> Understanding the molecular mechanisms of lymphangiogenesis, the role of the lymphatic system in different etiologies of liver disease, and the modulation of hepatic lymphatic system as strategy for treating liver disease and its complications. • Lymphatics of the heart -> Understanding lymphatic signaling vs. lymphatic drainage function during cardiac repair following MI, does lymphatic signaling affect other cell types in the heart during development of cardiac disease, understanding the origins of injury-induced lymphatic vessels, need to identify the novel players regulating lymphatic sprouting during embryonic development. • Lymphatics of the GI tract -> Understanding whether lymphatics of the GI are a conserved feature of epithelial cell niches (local microenvironment), does lymphatic intestinal stem cell communication respond dynamically to infection, inflammation, changes in nutrient availability. How do stem cells and crypt- based lymphatics regulate access of immune cells to the intestinal stem cell niche? How might stem cells regulate their lymphatic niche? How LECs sense and respond to tissue alterations, microbiome, and immune cues? What are the homeostatic LECs role in the intestine and its implication in disease? • Lymphatics of the kidneys -> Understanding the evidence that promotion of lymphangiogenesis is beneficial in several kidney diseases. Studies demonstrate that there is great heterogeneity of LECs across microvascular beds, vascular cell type, developmental stages, health vs. disease states. But why is that? ■ We need to better understand the lymphatic substrates (wall problem, valve problem, or pumping problem) that results in lymphatic failure with organ dysfunction (when lymph becomes dysfunctional how does it affect the organ). ■ We need to better understand the contribution of lymphatic dysfunction to end organ dysfunction. ■ We need to develop better treatment options for patients with lymphatic failure due to organ dysfunction.
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