b'4. Evaluation of Lymphatic Anatomy 8. The Role of the Lymphatic SystemHow is the nervous system involved in lymphaticin Different Organs of the Human Body communication, and in which ways does nervousin Health and in Disease system innervation impact lymphatic capacity, flow,How and why do lymphatics of certain organs become and function? dysfunctional, causing disease?Need to map the entire human lymphatic systemExamples of organ specific gaps in lymphatic in health and in disease. knowledge: What are the main lymphatic anatomy variants ofLymphatics of the eye - Understanding patho-the upper extremity, lower extremities, and thebody in general? physiology of glaucoma, retinal and optic nerve How does the presence or absence of any anatomicdiseases, and corneal transplant rejection. Lymphatics of the liver (a key organ of lymph variant potentially contribute to the incidence of lymphedema or other lymphatic diseases? production) - Understanding the molecular mechanisms of lymphangiogenesis, the role of the 5. Understanding Cellular Behavior lymphatic system in different etiologies of liver Explore role of lymphatic circulating tumor cellsdisease, and the modulation of hepatic lymphatic system as strategy for treating liver disease and(CTCs) from various metastatic tumors to clarify its complications. their parallel, hematogenous and lymphagenous dissemination, and role of various subpopulations ofLymphatics of the heart - Understanding lymphatic lymphatic CTCs (e.g., cancer stem cells) in metastasissignaling vs. lymphatic drainage function during progression. Also, uncover the pathways andcardiac repair following MI, does lymphatic signaling interactions between blood and lymphatic circulatingaffect other cell types in the heart during cells, exosomes, and other lymph components. development of cardiac disease, understanding the Use AI to develop models of cell behavior in aorigins of injury-induced lymphatic vessels, need to identify the novel players regulating lymphatic complex lymph microenvironment. sprouting during embryonic development.6. Need for Accurate and Widely Lymphatics of the GI tract - Understanding whetherAvailable Animal Models lymphatics of the GI are a conserved feature of epithelial cell niches (local microenvironment), does A major gap and need in studying lymphatics is thelymphatic intestinal stem cell communication respond availability of animal models that recapitulate thedynamically to infection, inflammation, changes in diverse biology and heterogeneity of humannutrient availability. How do stem cells and crypt-lymphatics (especially organ specific lymphatics inbased lymphatics regulate access of immune cells to health and disease). For example: aspects of mousethe intestinal stem cell niche? How might stem cells lymphatic physiology do not apply to humans; i.e.,regulate their lymphatic niche? How LECs sensevisceral and thoracic collecting lymphatics do notand respond to tissue alterations, microbiome, and pump, and mice are not exposed to chronicimmune cues? What are the homeostatic LECs rolegravitational loads. No animal models exist for thein the intestine and its implication in disease?human condition of lipedema.Lymphatics of the kidneys - Understanding the 7. Lymphatic Endothelial Cell (LEC)evidence that promotion of lymphangiogenesis is Specification beneficial in several kidney diseases. Studies demonstrate that there is great heterogeneity of Identify genes controlling the earliest steps ofLECs across microvascular beds, vascular cell type,lymphatic endothelial cell (LEC) specification. developmental stages, health vs. disease states.Development of in vitro systems to derive LECs fromBut why is that? human embryonic stem cells.We need to better understand the lymphatic Determine the plasticity of LEC phenotype and itssubstrates (wall problem, valve problem, orregulation by metabolic factors.pumping problem) that results in lymphatic failure with organ dysfunction (when lymph becomes We need to identify relevant molecules and cells dysfunctional how does it affect the organ).with which LECs communicate in vivo.How do mutant endothelial cells affect normalWe need to better understand the contribution oflymphatic dysfunction to end organ dysfunction. endothelial cells? How do complex lymphatic anomaly-causing We need to develop better treatment optionsfor patients with lymphatic failure due to organ genetic mutations affect different LEC populationsdysfunction. and how do mutant LECs affect normal LECs?|Gaps in the Field of Lymphatic Research|2024 Update|5'