The role of loading and the microenvironment on the regulation of lymphatic function and health

Abstract

The lymphatic system is composed of vessels and nodes and exists in almost all of the soft tissue of your body. It plays a large role in maintaining fluid homeostasis, immune cell trafficking, and lipid transport. Interstitial fluid that enters the lymphatic system through initial lymphatics is deemed “lymph” and is transported from the anatomical region where it is collected to the blood circulation. Unlike the venous system, lymphatic vessels must actively pump to drive lymph flow. Lymphatic dysfunction often leads to the development of swelling known as lymphedema. This buildup of fluid alters loading conditions of the local lymphatic network and lymphedema eventually leads to remodeling of the interstitium and lymphatic vessel walls. The extent to which remodeling of these extracellular matrices (ECM) is the cause and/or symptom of lymphatic dysfunction is not clearly understood. We present multiple studies utilizing engineering tools to better understand how the biomechanical properties and loading of the extracellular matrix regulate lymphatic function. We establish a healthy and remodelled lymphatic muscle cell (LMC) line and explore how LMC phenotype impact their response to 2D culture conditions. We demonstrate regulation of LMC molecular pathway expression via physiologically relevant levels of cyclic stretch. Modular poly(ethylene glycol) (PEG) based hydrogels are used to explore the sensitivity of sprouting lymphangiogenesis to properties of the extracellular matrix. PEG gels can be formulated to produce a robust sprouting network that is sensitive to a variety of molecular regulators. Finally, we present results demonstrating that the PEG hydrogels can be used to successfully transplant lymphatic tissue after damage to local lymphatic collecting vessel or lymph nodes. Tissue transplanted with this method becomes functionally incorporated into the local lymphatic network.