Lymphatic Pathophysiology

Abstract

Lymphatic research has rapidly accelerated and evolved over the last few decades with more clinicians and basic scientists appreciating the huge impact of this vasculature.1 The lymphatic system, with its network of vessels and interconnected nodes, returns interstitial fluid to the blood circulation and is central in the maintenance of fluid homeostasis, immune surveillance, and uptake of dietary lipids.2,3 The development of cuttingedge genetic models and imaging tools to manipulate and visualize lymphatic vessels, coupled with bioengineering approaches applied to the fundamental physiology of lymphatic vessel function, has significantly impacted our current understanding of the critical roles played by lymphatics both during development and in pathophysiological conditions across a plethora of disease states. This Special Topic Issue showcases a collection of primary research and review articles that highlight the diverse roles of lymphatics in disease pathogenesis that could potentially be leveraged to develop novel targeted approaches for therapeutic interventions. The primary research articles in the issue take various approaches to manipulate or target lymphatic vessel growth and function in disease. For example, the study by Michalaki et al.4 describes the therapeutic potential of engineered human mesenchymal stem cells overexpressing vascular endothelial growth factor C (VEGFC), as an autologous cellbased therapeutic treatment, for alleviation of lymphatic dysfunction associated with secondary injury mediated lymphedema. The study by Mahamud et al.5 shows that transcription factor GATA2 promotes blood/lymph separation through platelets and that while lymphovenous valves are the only known sites of interaction between blood and lymphatic vessels, more unidentified sites of interaction possibly exist between blood and lymphatic vessels. Steinskog et al.6 used a rat model mimicking acute myeloid leukemia (AML) with cannulation of efferent lymphatic vessels from the spleen and liver and subsequent proteomic profiling. Their findings revealed a differential response in AMLcell infiltrated spleen and liver, indicating that interstitial fluid and efferent lymph can provide unique information about the specific microenvironment responses that are variable in target organs during AML progression. In the work by Jo et al.,7 the effects of five different components which comprise Goreisan, a traditional herbal formulation (used as a therapeutic in Japan to alleviate lymphedema symptoms), were investigated for their effects on mesenteric lymphatic pumping in rats. They showed that that acute exposure of two components of Goreisan decreased lymphatic pumping in isolated rat mesenteric collecting lymphatics while oral administration of Goreisan induced vascular endothelial growth factor receptor 3 (VEGFR3), in these lymphatic vessels. Jablon et al.8 describe the development of an innovative technique for routine isolation, culture and characterization of primary lymphatic endothelial cells (LECs) from specific collecting vessels of mice, rats, and monkeys that maintain the endothelial functional phenotype. The study by Si et al.9 describes the effects of one of the most abundant venom components in the North American viper venom, crotamine, and reports that crotamine alters physiological behavior of LECs and lymphatic transport function. This work thus identifies how lymphatics are a major contributor to the pathology of snakebite both in the context of venom distribution and the resultant massive edema. The three review articles in this issue focus on innovative modeling and bioengineering approaches to study lymphatic function and pathology. The article by Suarez et al.10 focuses on describing and comparing lymphangiogenic outcomes and metrics between various in vitro and in vivo studies, with special emphasis on studies where both validation methods are used and identify pathological conditions where robust correlation is obtained. The review by Kraus and Lee11 provides a collective view of the evidence of the role of lymphatics in rheumatoid arthritis pathophysiology, and also enumerates existing attempts to replicate the synovium or lymphatics in vitro and how these elements may be synergistically applied. In a comprehensive review by Selahi and Jain,12 a broad range of ex vivo and in vitro engineered models are highlighted and compared, based on the major lymphatic function they model such as contractile function, inflammation, drainage and immune regulation, lymphangiogenesis, and tumorlymphatic interactions. The authors also provide a detailed overview on existing microfluidic devices and in vitro platforms that are used to study different facets of lymphatic functional crosstalk with the surrounding stromal cells, tumor cells, or immune cells in a specific tissue microenvironment. Collectively, the articles in this Special Topic Issue, cover a very broad range of research emphasizing potential future approaches aimed towards manipulating lymphatic vessels to lessen or ameliorate disease pathogenesis. This work represents the promising trajectory and growth of lymphatic research and underscores the fact that the lymphatics have finally garnered the attention that such an important part of the circulatory system deserves, given its involvement in critical physiological functions. We are indebted to all the authors for their contributions and efforts in highlighting this rapidly evolving frontier of microcirculation research.