Leveraging Biomaterials and Cellular Engineering to Advance Lymphatic Research and Therapeutics

The mammalian lymphatic system represents a complex and vital vascular network, intricately woven throughout the body's tissues, operating in parallel yet distinctly from the high-pressure, closed-loop blood circulatory system. While often overshadowed by its counterpart, the lymphatic vasculature performs indispensable roles in maintaining physiological equilibrium. It is fundamentally involved in regulating tissue fluid homeostasis, orchestrating immune cell trafficking and surveillance, facilitating the absorption and transport of dietary lipids, and participating in metabolic processes. Comprising specialized vessels and lymphoid organs—including lymph nodes, the spleen, thymus, and tonsils—this network is crucial for overall health. Dysfunction or maldevelopment of the lymphatic system is increasingly recognized as a key contributor to the pathophysiology of a diverse array of human diseases, ranging from debilitating lymphedema and cancer metastasis to inflammatory conditions, cardiovascular disorders like atherosclerosis, and metabolic disturbances including obesity and diabetes. Despite its profound physiological significance and pathological relevance, our understanding of lymphatic biology, particularly the molecular mechanisms governing the specification, differentiation, and maintenance of lymphatic endothelial cells (LECs) – the primary cellular constituents of lymphatic vessels – remains limited. Progress in the field is significantly hampered by persistent challenges, including the difficulty of maintaining LEC phenotypic stability in standard in vitro culture conditions and the scarcity of reliable, scalable sources of functional, patient-specific LECs for research and potential therapeutic applications. This dissertation aims to address these critical limitations by developing novel biomaterial-based platforms to preserve LEC characteristics in vitro, establishing efficient protocols for generating LECs from human induced pluripotent stem cells (hiPSCs), and investigating fundamental cellular signaling mechanisms that regulate LEC differentiation. By overcoming these bottlenecks, this work seeks to provide essential tools and knowledge to advance the study of lymphatic biology and its role in health and disease.