Abstract
One-way valves in the lymphatic system form from lymphatic endothelial cells (LECs) during embryonic development and are required for efficient tissue drainage. Although fluid flow is thought to guide both valve formation and maintenance, how this occurs at a mechanistic level remains incompletely understood. We built microfluidic devices that reproduce critical aspects of the fluid flow patterns found at sites of valvulogenesis. Using these devices, we observed that LECs replicated aspects of the early steps in valvulogenesis: cells oriented perpendicular to flow in the region of maximum wall shear stress (WSS) and exhibited enhanced nuclear localization of FOXC2, a transcription factor required for valvulogenesis. Further experiments revealed that the cell surface protein E-selectin was required for both of these responses. Our observations suggest that spatial gradients in WSS help to demarcate the locations of valve formation, and implicate E-selectin as a component of a mechanosensory process for detecting WSS gradients.
Highlights
One-way valves in the lymphatic system form from lymphatic endothelial cells (LECs) during embryonic development and are required for efficient tissue drainage
Lymphatic valve formation occurs through distinct steps that include upregulation of PROX1 and FOXC2, two transcription factors required for valve formation, alignment of lymphatic endothelial cells (LECs) perpendicular to the flow direction, increased deposition of laminin α5, and nuclear localization of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1)[7,8,9]
Other geometries with various length scales and constriction types were tested, we settled on the presented design because it facilitated reproducible fabrication and live-cell imaging while generating a sharp gradient in wall shear stress (WSS) similar to those found in the lymphatic system
Summary
One-way valves in the lymphatic system form from lymphatic endothelial cells (LECs) during embryonic development and are required for efficient tissue drainage. Lymphatic valve formation occurs through distinct steps that include upregulation of PROX1 and FOXC2, two transcription factors required for valve formation, alignment of lymphatic endothelial cells (LECs) perpendicular to the flow direction, increased deposition of laminin α5, and nuclear localization of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1)[7,8,9]. Both the formation and maintenance of lymphatic valves are governed by fluid flow[9,10]. Devices such as we describe may prove generally useful for in vitro reconstitution of the physical stimuli present within the lymphatic system, and most at sites of valve formation
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