Associate Professor Texas A&M University College Station, Texas, United States
Introduction: Despite the crucial role of the lymphatic vascular system during development and in several diseases with implications for tissue regeneration, immunity, and cancer, there are significantly fewer tools to understand this process relative to blood microcirculation. For example, while there has been a major surge in modeling angiogenesis with microphysiological systems, they have not been rigorously optimized or standardized to enable the recreation of the dynamics of lymphangiogenesis. My lab has recently engineered a living Lymphangion-Chip and a Lymphangiogenesis-Chip platform that reveals the independent and combinatorial regulation of the mechanical and biochemical determinants of the physiology of these biological systems.
Materials and
Methods: We use methods and approaches used to design and engineer organ-on-chip systems. Specifically, these systems leverage our patented Gravitational Lumen Patterning (GLP) technique supporting a formation of a lumen surrounded by a thick extracellular matrix. We can co-culture endothelial cells lining the inner wall of the ECM and embed perivascular cells, for example, lymphatic muscle cells within the ECM. Using either commercial syringe pumps or our own design, we perfuse media, reagents, stimulants or drugs under uniform or pulsatile flow.
Results, Conclusions, and Discussions: The Lymphangion-Chip consists of co-culture of a monolayer of endothelial lumen surrounded by multiple and uniformly thick layers of muscle cells. The platform allows construction of a wide range of luminal diameters and muscular layer thicknesses, thus providing a toolbox to create variable anatomy. In this device, lymphatic muscle cells align circumferentially while endothelial cells aligned axially under flow, as only observed in vivo in the past. This system successfully characterizes the dynamics of cell size, density, growth, alignment, and intercellular gap due to co-culture and shear. Finally, exposure to pro-inflammatory cytokines reveals that the device could produce the regulation of endothelial barrier function through the lymphatic muscle cells. In the Lymphangiogenesis-Chip, when we dissected the constitution of the inflammatory pretreatment and growth factor cocktail used to initiate and promote lymphangiogenesis, we found that endocan (ESM1) is a more specific regulator of lymphangiogenesis relative to angiogenesis.
These foundational organ-on-chip technologies built in my lab and also by other academic peer groups require scientific equity to mature the basic and translational science of lymphatics at par with the blood vasculature.
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