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Background: In heart failure, the capacity of the lymphatic system dictates symptoms of circulatory congestion. This study aimed at describing structural and functional changes of the lymphatic system in patients with chronic right-sided heart failure., Methods: Individuals with long-standing severe tricuspid valve regurgitation and symptoms of heart failure were compared with age- gender- and weight-matched controls. Lymphatic structure and function were examined using non-contrast MR lymphangiography and near-infrared fluorescence imaging. Microvascular fluid dynamics and distribution were evaluated using strain gauge plethysmography and bio-impedance., Results: In total nine patients and nine controls were included. Lymphatic morphology was unchanged in cases compared to controls with similar thoracic duct diameters 3.1(2.1-3.5) mm vs. 2.0(1.8-2.4) mm (p-value = 0.11), similar lymphatic classifications (p-value 0.34), and an identical number of lymphatic vessels in the legs 6 ± 1 vs. 6 ± 3 vessels/field (p-value = 0.72). Lymphatic function was comparable with contraction frequencies of 0.5 ± 0.2 and 0.5 ± 0.3 /min (p-value = 0.52) and a maximal lymphatic pumping pressure of 60 ± 13 and 57 ± 12 mmHg (p-value = 0.59) for cases and controls respectively. Finally, microvascular capillary filtration, isovolumetric threshold, and fluid distribution were similar between groups (p-value≥0.16 for all comparisons)., Conclusion: In this small exploratory study, individuals with severe secondary tricuspid valve regurgitation and right-sided heart failure displayed a largely similar lymphatic anatomy and function. Thoracic duct diameter displayed a trend towards increased size in the patient group. We speculate that cases were indeed stable and optimally treated at the time of examination, and with a lymphatic system largely unaffected by any of the current or prior hemodynamic changes., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the role of the paravertebral lymphatic system in the nucleus pulposus herniation (NPH) resorption and the inflammation regression., Design: Clinical specimens (n = 10) from patients with lumbar disc herniation (LDH) were collected, C57BL/6 (n = 84) and conditional Vegfr3 knockout mice (n = 14) were used. Immunofluorescence staining detected lymphatic vessels (LVs) and NP cells. Near-infrared imaging assessed lymphatic drainage function, and Alcian Blue/Orange determined inflammation., Results: Lymphangiogenesis was observed in the herniated NP of patients with LDH, and the proportion of capillary LVs was higher than that of collecting LVs (mean 68.2% [95% confidence interval: 59.4, 77.1]). In NPH mice, NP cells were detected in paravertebral tissue (38.6 [32.0, 45.2]) and draining lymph nodes (dLN) at 4 h (76.9 [54.9, 98.8]). A significant increase of NP cells in dLNs was observed at 24 h (157.1 [113.7, 200.6]). Most of the herniated NP cells were cleared in paravertebral tissue after 1 week (7.5 [4.4, 10.6]), but disc inflammation peaked at 1 week (19.9% [14.7, 25.1]), along with persistent lymphangiogenesis (9.5 [7.2, 11.8]). However, conditional Vegfr3 knockout mice exhibited impaired lymphangiogenesis (5.7 [4.4, 7.0]) and herniated NP cell clearance (6.1 [1.8, 10.5]) during NPH, leading to exacerbated disc inflammation (23.7% [19.3, 28.2])., Conclusion: The paravertebral lymphatic system is involved in the NPH resorption and inflammation regression. Promoting lymphangiogenesis may be a novel strategy for facilitating NPH resorption and inflammation regression in patients with LDH., (Copyright © 2024 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Cancer dissemination to lymph nodes (LN) is associated with a worse prognosis, increased incidence of distant metastases and reduced response to therapy. The LN microenvironment puts selective pressure on cancer cells, creating cells that can survive in LN as well as providing survival advantages for distant metastatic spread. Additionally, the presence of cancer cells leads to an immunosuppressive LN microenvironment, favoring the evasion of anti-cancer immune surveillance. However, recent studies have also characterized previously unrecognized roles for tumor-draining lymph nodes (TDLNs) in cancer immunotherapy response, including acting as a reservoir for pre-exhausted CD8+ T cells and stem-like CD8+ T cells. In this review, we will discuss the spread of cancer cells through the lymphatic system, the roles of TDLNs in metastasis and anti-cancer immune responses, and the therapeutic opportunities and challenges in targeting LN metastasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lei, Fraser, Jones, Ubellacker and Padera.)

We aimed to evaluate the role of the spinal lymphatic system in spinal cord injury and whether it has an impact on recovery after spinal cord injury. Flow cytometry was used to evaluate the changes in the number of microvesicles after spinal cord injury. Evans blue extravasation was used to evaluate the function of the lymphatic system. Evans blue extravasation and immunofluorescence were used to evaluate the permeability of blood spinal cord barrier. The spinal cord edema was evaluated by dry and wet weight.Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay was used to evaluate apoptosis after spinal cord injury. Nuclear factor-kappa B pathway was detected by Western blot. Behavioral tests were used to evaluate limb function. Microvesicles released after spinal cord injury can enter the thoracic duct and then enter the blood through the lymph around the spine. After ligation of the thoracic duct, it can aggravate the neuropathological manifestations and limb function after spinal cord injury. The potential mechanism may involve nuclear factor-kappa B pathway., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background:  Alzheimer's disease (AD) is pathologically characterized by the abnormal accumulation of Aβ and tau proteins. There has long been a keen interest among researchers in understanding how Aβ and tau are ultimately cleared in the brain. The discovery of this glymphatic system introduced a novel perspective on protein clearance and it gained recognition as one of the major brain clearance pathways for clearing these pathogenic proteins in AD. This finding has sparked interest in exploring the potential contribution of the glymphatic/meningeal lymphatic system in AD. Furthermore, there is a growing emphasis and discussion regarding the possibility that activating the glymphatic/meningeal lymphatic system could serve as a novel therapeutic strategy against AD., Objectives:  Given this current research trend, the primary focus of this comprehensive review is to highlight the role of the glymphatic/meningeal lymphatic system in the pathogenesis of AD. The discussion will encompass future research directions and prospects for treatment in relation to the glymphatic/meningeal lymphatic system., (© 2024. The Author(s).)

Numerous evidence has demonstrated that the brain is not an immune-privileged organ but possesses a whole set of lymphatic transport system, which facilitates the drainage of harmful waste from brains to maintain cerebral homeostasis. However, as individuals age, the shrinkage and dysfunction of meningeal and deep cervical lymphatic networks lead to reduced waste outflow and elevated neurotoxic molecules deposition, further inducing aging-associated cognitive decline, which act as one of the pathological mechanisms of Alzheimer's disease. Consequently, recovering the function of meningeal and deep cervical lymph node (dCLNs) networks (as an important part of the brain waste removal system (BWRS)) of aged brains might be a feasible strategy. Herein we showed that the drug brain-entering efficiency was highly related to administration routes (oral, subcutaneous, or dCLN delivery). Besides, by injecting a long-acting lyotropic liquid crystalline implant encapsulating cilostazol (an FDA-approved selective PDE-3 inhibitor) and donepezil hydrochloride (a commonly used symptomatic relief agent to inhibit acetylcholinesterase for Alzheimer's disease) near the deep cervical lymph nodes of aged mice (about 20 months), an increase of lymphatic vessel coverage in the nodes and meninges was observed, along with accelerated drainage of macromolecules from brains. Compared with daily oral delivery of cilostazol and donepezil hydrochloride, a single administered dual drugs-loaded long-acting implants releasing for more than one month not only elevated drug concentrations in brains, improved the clearing efficiency of brain macromolecules, reduced Aβ accumulation, enhanced cognitive functions of the aged mice, but improved patient compliance as well, which provided a clinically accessible therapeutic strategy toward aged Alzheimer's diseases.

The lymphatic kidney system plays a crucial role in managing interstitial fluid removal, regulating fluid balance, and tuning immune response. It also assists in the reabsorption of proteins, electrolytes, cytokines, growth factors, and immune cells. Pathological conditions, including tissue damage, excessive interstitial fluid, high blood glucose levels, and inflammation, can initiate lymphangiogenesis-the formation of new lymphatic vessels. This process is associated with various kidney diseases, including polycystic kidney disease, hypertension, ultrafiltration challenges, and complications post-organ transplantation. Although lymphangiogenesis has beneficial effects in removing excess fluid and immune cells, it may also contribute to inflammation and fibrosis within the kidneys. In this review, we aim to discuss the biology of the lymphatic system, from its development and function to its response to disease stimuli, with an emphasis on renal pathophysiology. Furthermore, we explore how innovative treatments targeting the lymphatic system could potentially enhance the management of kidney diseases.

Lymphatic flow and anatomy can be challenging to study, owing to variable lymphatic anatomy in patients with diverse primary or secondary lymphatic pathologic conditions and the fact that lymphatic imaging is rarely performed in healthy individuals. The primary components of the lymphatic system outside the head and neck are the peripheral, retroperitoneal, mesenteric, hepatic, and pulmonary lymphatic systems and the thoracic duct. Multiple techniques have been developed for imaging components of the lymphatic system over the past century, with trade-offs in spatial, temporal, and contrast resolution; invasiveness; exposure to ionizing radiation; and the ability to obtain information on dynamic lymphatic flow. More recently, dynamic contrast-enhanced (DCE) MR lymphangiography (MRL) has emerged as a valuable tool for imaging both lymphatic flow and anatomy in a variety of congenital and acquired primary or secondary lymphatic disorders. The authors provide a brief overview of lymphatic physiology, anatomy, and imaging techniques. Next, an overview of DCE MRL and the development of an MRL practice and workflow in a hybrid interventional MRI suite incorporating cart-based in-room US is provided, with an emphasis on multidisciplinary collaboration. The spectrum of congenital and acquired lymphatic disorders encountered early in an MRL practice is provided, with emphasis on the diversity of imaging findings and how DCE MRL can aid in diagnosis and treatment of these patients. Methods such as DCE MRL for assessing the hepatic and mesenteric lymphatic systems and emerging technologies that may further expand DCE MRL use such as three-dimensional printing are introduced. © RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Advances in lymphatic imaging for both diagnosis and intervention are reviewed, and specific examples given for protein-losing enteropathy, multi compartment lymphatic failure, congestive heart failure. Presented at the 2023 ISL International Congress of Lymphology, Genoa, Italy in a special symposium on central and regional lymphatic system in health and disease., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by International Society of Lymphology.)

Lymphatic anatomy of the abdomen is reviewed with focus on hepatic and mesenteric vessels in normal and pathologic conditions. Anatomy and pathophysiology is highlight using both specialized fluoroscopy and T2 Dynamic Contrast MR lymphangiography (DCMRL). Plastic bronchitis, chylothorax, protein losing enteropathy, and both cirrhosis and ascites due to hepatic lymphatics are highlighted. Presented at the 2023 ISL International Congress of Lymphology, Genoa, Italy in a special symposium on central and regional lymphatic system in health and disease., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by International Society of Lymphology.)

The brain's lymphatic system is comprised of a glymphatic-meningeal-cervical lymphatic vessel pathway. The study of its mechanism and pathophysiology in neurodegenerative disease has been one of the most exciting topics in basic and translational neuroscience of the last decade. However, while there has been some debate about when the meningeal lymphatics were discovered, it cannot be denied that studies in preclinical models and humans in this century represent a monumental step forward in our understanding of how the brain removes metabolic waste, the role this system plays in neurodegenerative disease, and, most importantly, its potential as a novel therapeutic target. This is a summary of the history, functional anatomy, and role of the brain's lymphatics in neurodegenerative disease., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by International Society of Lymphology.)

Contractile function of the collecting lymphatic vessels depend on smooth muscle cells, one-way valves, surrounding tissues, and regulation by the autonomic nervous system. The potentially deleterious effects of the Fontan procedure and elevated central venous pressure on lymphatic function leading to life-threatening complications are described. Presented at the 2023 ISL International Congress of Lymphology, Genoa, Italy in a special symposium on central and regional lymphatic system in health and disease., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by International Society of Lymphology.)

Central lymphatic disorders of the lung have not received intense investigation. Lymphatic system physiology is presented in the context of historical developments and basic lung lymphatic anatomy is reviewed followed by emerging characteristics of primary and secondary pathophysiological disturbances of lymphatic involvement in a number of pulmonary diseases including Gorham-Stout disease, pulmonary edema and infections and inflammatory conditions including lymphangioleiomyomatosis (LAM). The future includes potential molecular targeting of lymphangiogenesis or lymphatic vessels for interventional occlusion. This article is an amalgamation of presentations at the 2023 ISL International Congress of Lymphology, Genoa, Italy in a special symposium on central and regional lymphatic system in health and disease and as part of a Special Symposium on the Lymphatic system of the Heart and Lung in Health and Disease at the 26th International Congress of Lymphology meeting held in Barcelona, Spain, September 2017, which has been updated to 2024., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by International Society of Lymphology.)

Lymphatic flow disorders are reviewed, and a classification based on magnetic resonance lymphography findings outlined. Examples of successful interventional management based on this classification are provided. Presented at the 2023 ISL International Congress of Lymphology, Genoa, Italy in a special symposium on central and regional lymphatic system in health and disease., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by International Society of Lymphology.)

Background: Post-mastectomy lymphedema is a chronic progressive disease characterized by a significant reduction in quality of life and a range of complications., Aim: To this date, no single treatment method provides pathological correction of the mechanisms associated with tissue reorganization observed in later-stage breast cancer-related lymphedema (BCRL)., Methods: To define a personalized approach to the management of patients with iatrogenic lymphedema, we performed a systematic review of literature without a comprehensive meta-analysis to outline existing molecular- genetic patterns, overview current treatment methods and their efficacy, and highlight the specific tissue-associated changes in BCRL conditions and other bio-engineering approaches to develop personalized therapy., Results: Our results show that several tissue-specific and pathological molecular markers may be found, yet current research does not aim to define them., Conclusion: As such, currently, a strong foundation for further research into molecular-genetic changes in lymphedema tissue exists, and further research should focus on finding specific targets for personalized treatment through bio-engineering approaches., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Lymphatic flow disorders are rare but devastating complications in children with congenital heart disease. T2-weighted magnetic resonance lymphography and intranodal dynamic contrast magnetic resonance lymphangiography are imaging modalities that can depict central lymphatic anatomy and flow pattern. Our objective was to describe the technical aspects and our imaging findings of central lymphatic abnormalities and their impact on patient management and outcomes: We conducted a retrospective review of 26 children with congenital heart disease who presented for lymphatic imaging between 2015 and 2020 at our institution. Eleven had postoperative chylothorax, six had plastic bronchitis, seven had protein-losing enteropathy and three had Noonan syndrome. Our lymphatic imaging demonstrated severely abnormal lymphatic flow in all of the children, but only minor abnormalities in protein-losing enteropathy. No major procedure-related complication occurred. Lymphatic interventions were performed in six patients, thoracic duct decompression in two patients and chylothorax revision in three patients. This led to symptomatic improvements in all of the patients: Lymphatic imaging is safe and essential for the diagnosis of lymphatic flow disorders and therapy planning. Our intranodal lymphangiography depicts an abnormal lymphatic flow pattern from the central lymphatics but failed to demonstrate an abnormal lymphatic flow in protein-losing enteropathy. These imaging techniques are the basis for selective lymphatic interventions, which are promising to treat lymphatic flow disorders.

Alzheimer's disease (AD) is an aging-related form of dementia associated with the accumulation of pathological aggregates of amyloid beta and neurofibrillary tangles in the brain. These phenomena are accompanied by exacerbated inflammation and marked neuronal loss, which altogether contribute to accelerated cognitive decline. The multifactorial nature of AD, allied to our still limited knowledge of its etiology and pathophysiology, have lessened our capacity to develop effective treatments for AD patients. Over the last few decades, genome wide association studies and biomarker development, alongside mechanistic experiments involving animal models, have identified different immune components that play key roles in the modulation of brain pathology in AD, affecting its progression and severity. As we will relay in this review, much of the recent efforts have been directed to better understanding the role of brain innate immunity, and particularly of microglia. However, and despite the lack of diversity within brain resident immune cells, the brain border tissues, especially the meninges, harbour a considerable number of different types and subtypes of adaptive and innate immune cells. Alongside microglia, which have taken the centre stage as important players in AD research, there is new and exciting evidence pointing to adaptive immune cells, namely T and B cells found in the brain and its meninges, as important modulators of neuroinflammation and neuronal (dys)function in AD. Importantly, a genuine and functional lymphatic vascular network is present around the brain in the outermost meningeal layer, the dura. The meningeal lymphatics are directly connected to the peripheral lymphatic system in different mammalian species, including humans, and play a crucial role in preserving a "healthy" immune surveillance of the CNS, by shaping immune responses, not only locally at the meninges, but also at the level of the brain tissue. In this review, we will provide a comprehensive view on our current knowledge about the meningeal lymphatic vasculature, emphasizing its described roles in modulating CNS fluid and macromolecule drainage, meningeal and brain immunity, as well as glial and neuronal function in aging and in AD., (© 2023. Editorial Group and BioMed Central Ltd., part of Springer Nature.)

Fibrosis occurs in many chronic diseases with lymphatic vascular insufficiency (e.g., kidney disease, tumors, and lymphedema). New lymphatic capillary growth can be triggered by fibrosis-related tissue stiffening and soluble factors, but questions remain for how related biomechanical, biophysical, and biochemical cues affect lymphatic vascular growth and function. The current preclinical standard for studying lymphatics is animal modeling, but in vitro and in vivo outcomes often do not align. In vitro models can also be limited in their ability to separate vascular growth and function as individual outcomes, and fibrosis is not traditionally included in model design. Tissue engineering provides an opportunity to address in vitro limitations and mimic microenvironmental features that impact lymphatic vasculature. This review discusses fibrosis-related lymphatic vascular growth and function in disease and the current state of in vitro lymphatic vascular models while highlighting relevant knowledge gaps. Additional insights into the future of in vitro lymphatic vascular models demonstrate how prioritizing fibrosis alongside lymphatics will help capture the complexity and dynamics of lymphatics in disease. Overall, this review aims to emphasize that an advanced understanding of lymphatics within a fibrotic disease-enabled through more accurate preclinical modeling-will significantly impact therapeutic development toward restoring lymphatic vessel growth and function in patients., (© 2023 The Authors. Advanced Biology published by Wiley-VCH GmbH.)

Lymph node metastasis is the most important prognostic factor in patients with lung squamous cell carcinoma. The current findings show that lymph node metastatic tumor cells can arise by programming metastasis in primary tumor cells. Thereby, the genetic alterations responsible for the metastasis could be detected in the primary tumors. This bioinformatic study aimed to determine novel potential prognostic biomarkers shared between primary lung squamous cell tumors (without lymph node metastasis) and lymphatic metastasis, using the Cancer Genome Atlas database. Differentially expressed genes were screened by limma statistical package in R environment. Gene ontology and biological pathways analyses were performed using Enrichr for up-regulated and down-regulated genes. Also, we selected lymph node metastasis related genes among DEGs using correlation analysis between DEGs and suitable references genes for metastasis. Receiver operating characteristic curves was applied using pROC and R package ggplot2 to evaluate diagnostic value of differentially expressed genes. In addition, survival and drug resistance analyses were performed for differentially expressed genes. The miRNA-mRNA interaction networks were predicted by miRwalk and TargetScan databases and expression levels analysis of the miRNAs which were mainly targeting mRNAs was performed using UALCAN database. Protein-protein interaction network analysis and hub genes identification were performed using FunRich and Cytoscape plugin cytoHubba. In this study, a total of 397 genes were differentially expressed not only with a significant difference between N + vs. normal and N0 vs. normal but also with significant difference between N + vs. N0. Identified GO terms and biological pathways were consistent with DEGs role in the lung squamous cell carcinoma and lymph node metastasis. A significant correlation between 56 genes out of 397 differentially expressed genes with reference genes prompted them being considered for identifying lymph node metastasis of lung squamous cell carcinoma. In addition, SLC46A2, ZNF367, AC107214.1 and NCBP1 genes were identified as survival-related genes of patients with lung squamous cell carcinoma. Moreover, NEDD9, MRPL21, SNRPF, and SCLT1 genes were identified to be involved in lung squamous cell carcinoma drug sensitivity/resistance. We have identified several numbers of miRNAs and their related target genes which could emerge as potential diagnostic biomarkers. Finally, CDK1, PLK1, PCNA, ZWINT and NDC80 identified as hub genes for underlying molecular mechanisms of lung squamous cell carcinoma and lymphatic metastasis. Our study highlights new target genes according to their relation to lymph node metastasis, whose expressions in the primary lung squamous cell carcinoma are able to accurately assess the presence of lymphatic metastasis., (© 2023. The Author(s).)

Understanding and treating Alzheimer's disease (AD) has been a remarkable challenge for both scientists and physicians. Although the amyloid-beta and tau protein hypothesis have largely explained the key pathological features of the disease, the mechanisms by which such proteins accumulate and lead to disease progression are still unknown. Such lack of understanding disrupts the development of disease-modifying interventions, leaving a therapeutic gap that remains unsolved. Nonetheless, the recent discoveries of the glymphatic pathway and the meningeal lymphatic system as key components driving central solute clearance revealed another mechanism underlying AD pathogenesis. In this regard, this narrative review integrates the glymphatic and meningeal lymphatic systems as essential components involved in AD pathogenesis. Moreover, it discusses the emerging evidence suggesting that nutritional supplementation, non-invasive brain stimulation, and traditional Chinese medicine can improve the pathophysiology of the disease by increasing glymphatic and/or meningeal lymphatic function. Given that physical exercise is a well-regarded preventive and pro-cognitive intervention for dementia, we summarize the evidence suggesting the glymphatic system as a mediating mechanism of the physical exercise therapeutic effects in AD. Targeting these central solute clearance systems holds the promise of more effective treatment strategies., (© 2023. The Author(s).)

Lymphedema is a chronic condition of impaired lymphatic flow that results in limb swelling and debilitation. The pathophysiology of lymphedema is characterized by lymphatic stasis that triggers inflammation, fibrosis, and adipose tissue deposition in the extremities. Most often, this condition occurs in cancer survivors in the years after treatment with combinations of surgery, radiation, or chemotherapy, with the major risk factor being lymph node dissection. Interestingly, obesity and body mass index are independent risk factors for development of lymphedema, suggesting interactions between adipose and lymphatic tissue biology. Currently, treatment of lymphedema involves palliative approaches, including compression garments and physical therapy, and surgical approaches, including liposuction, lymphovenous bypass, and vascularized lymph node transfer. Emerging lymphedema therapies that focus on weight loss or reducing inflammation have been tested in recent clinical trials, yielding mixed results with no effect on limb volumes or changes in bioimpedance measurements. These studies highlight the need for novel therapeutic strategies that target the driving forces of lymphedema. In this light, animal models of lymphedema demonstrate a role of adipose tissue in the progression of lymphedema and suggest these processes may be targeted in the treatment of lymphedema. Herein, we review both conventional and experimental therapies for lymphedema as well as the defining characteristics of its pathophysiology. We place emphasis on the aberrant fibroadipose tissue accumulation in lymphedema and propose a new approach to experimental treatment at the level of adipocyte metabolism.

The draining of brain interstitial fluid (ISF) to cerebrospinal fluid (CSF) and the subsequent draining of CSF to meningeal lymphatics is well-known. Nonetheless, its role in the development of glioma is a remarkable finding that has to be extensively understood. The glymphatic system (GS) collects CSF from the subarachnoid space and brain ISF through aquaporin-4 (AQP4) water channels. The glial limiting membrane and the perivascular astrocyte-end-feet membrane both have elevated levels of AQP4. CSF is thought to drain through the nerve sheaths of the olfactory and other cranial nerves as well as spinal meningeal lymphatics via dorsal or basal lymphatic vessels. Meningeal lymphatic vessels (MLVs) exist below the skull in the dorsal and basal regions. In this view, MLVs offer a pathway to drain macromolecules and traffic immunological cells from the CNS into cervical lymph nodes (CLNs), and thus can be used as a candidate curing strategy against glioma and other associated complications, such as neuro-inflammation. Taken together, the lymphatic drainage system could provide a route or approach for drug targeting of glioma and other neurological conditions. Nevertheless, its pathophysiological role in glioma remains elusive, which needs extensive research. The current review aims to explore the lymphatic drainage system, its role in glioma progression, and possible therapeutic techniques that target MLVs in the CNS., (© 2022 John Wiley & Sons Ltd.)

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Pathological deposits of neurotoxic proteins within the brain, such as amyloid-ß and hyperphosphorylated tau tangles, are the prominent features in AD. According to recent studies, the newly discovered brain lymphatic system was demonstrated to be crucial in the clearance of metabolic macromolecules from the brain. Meningeal lymphatic vessels located in the dura mater drain the fluid, macromolecules, and immune cells from cerebrospinal fluid (CSF) and transport them, as lymph, to the deep cervical lymph nodes. The lymphatic system provides the perivascular exchange of CSF with interstitial fluid (ISF) and ensures the homeostasis of neuronal interstitial space. In this review, we aim to summarize recent findings on the role of the lymphatic system in AD pathophysiology and discuss possible therapeutic perspectives, targeting the lymphatic clearance mechanisms within the brain., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Meningeal lymphatic vessels (mLVs), the functional lymphatic system present in the meninges, are the key drainage route responsible for the clearance of molecules, immune cells, and cellular debris from the cerebrospinal fluid and interstitial fluid into deep cervical lymph nodes. Aging and ApoE4, the two most important risk factors for Alzheimer's disease (AD), induce mLV dysfunction, decrease cerebrospinal fluid influx and outflux, and exacerbate amyloid pathology and cognitive dysfunction. Dysfunction of mLVs results in the deposition of metabolic products, accelerates neuroinflammation, and promotes the release of pro-inflammatory cytokines in the brain. Thus, mLVs represent a novel therapeutic target for treating neurodegenerative and neuroinflammatory diseases. This review aims to summarize the structure and function of mLVs and to discuss the potential effect of aging and ApoE4 on mLV dysfunction, as well as their roles in the pathogenesis of AD.

Although metastatic melanoma can be managed with chemotherapy, its heterogeneity and resistance to therapy remain poorly understood. In addition to the spread of melanoma in the bloodstream, melanoma-stroma interaction and the lymphatic system play active roles in said heterogeneity and resistance, leading to its progression and metastasis. Reproducing the complexities of the melanoma microenvironment in vitro will help understanding its progression and enhance the translatability of potential cancer therapeutics. A blood-lymphatic integrated system with heterogeneous melanoma spheroids (BLISH) using the in-bath bioprinting process is developed. The process uniformly prints size-controllable metastatic melanoma spheroids along with biomimetic blood and lymphatic vessels (LVs). The system reproduces hallmark events of metastatic melanoma, such as tumor stroma interaction, melanoma invasion, and intravasation. The application of the system to investigate the anticancer effect of combinational targeted therapy suggests that it can be used to study the pathophysiology of melanoma and improve the accuracy of drug response monitoring in skin cancer., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Lymphedema is a progressive disease caused by lymphatic flow blockage in the lymphatic pathway. Primary (hereditary) lymphedema is caused by genetic mutations without secondary causes. We performed clinical profiling on Korean primary lymphedema patients based on their phenotypes using lymphoscintigraphy and made genetic diagnoses using a next-generation sequencing panel consisting of 60 genes known to be related to primary lymphedema and vascular anomalies. Of 27 patients included in this study, 14.8% of the patients had lymphedema of the upper extremities, 77.8% had lymphedema of the lower extremities and 7.4% had 4-limbs lymphedema. Based on the International Society of Lymphology staging, 14, 10, and 3 patients had stage 3, 2, and 1 lymphedema, respectively. Only one family was genetically confirmed to harbor likely pathogenic variants in CELSR1. The proband was carrying two likely pathogenic variants in CELSR1, while her symptomatic mother was confirmed to carry only one of the variants. Furthermore, two other variants of uncertain significance in CELSR1 were detected in other patients, making CELSR1 the most commonly altered gene in our study. The clinical and genetic profile of hereditary lymphedema reported here is the first such data series reported for South Korea., (© 2022. The Author(s).)

Significance: Lymphedema is a common disease that affects hundreds of millions of people worldwide with significant financial and social burdens. Despite increasing prevalence and associated morbidities, the mainstay treatment of lymphedema is largely palliative without an effective cure due to incomplete understanding of the disease. Recent Advances: Recent studies have described key histological and pathological processes that contribute to the progression of lymphedema, including lymphatic stasis, inflammation, adipose tissue deposition, and fibrosis. This review aims to highlight cellular and molecular mechanisms involved in each of these pathological processes. Critical Issues: Despite recent advances in the understanding of the pathophysiology of lymphedema, cellular and molecular mechanisms underlying the disease remains elusive due to its complex nature. Future Directions: Additional research is needed to gain a better insight into the cellular and molecular mechanisms underlying the pathophysiology of lymphedema, which will guide the development of therapeutic strategies that target specific pathology of the disease.

As an integral part of the vascular system, the lymphatic vasculature is essential for tissue fluid homeostasis, nutritional lipid assimilation and immune regulation. The composition of the lymphatic vasculature includes fluid-absorbing initial lymphatic vessels (LVs), transporting collecting vessels and anti-regurgitation valves. Although, in recent decades, research has drastically enlightened our view of LVs, investigations of initial LVs, also known as lymphatic capillaries, have been stagnant due to technical limitations. In the kidney, the lymphatic vasculature mainly presents in the cortex, keeping the local balance of fluid, solutes and immune cells. The contribution of renal LVs to various forms of pathology, especially chronic kidney diseases, has been addressed in previous studies, however with diverging and inconclusive results. In this review, we discuss the most recent advances in the proliferation and permeability of lymphatic capillaries as well as their influencing factors. Novel technologies to visualize and measure LVs function are described. Then, we highlight the role of the lymphatic network in renal fibrosis and the crosstalk between kidney and other organs, such as gut and heart.

Background: The lymphatic system consists of the superficial and deep lymphatic system. Several diagnostic methods are used to assess the lymphatic system. Lymphoscintigraphy and indocyanine green lymphography are widely applied, both showing disadvantages, such as a poor resolution and lack of field of view. Magnetic resonance lymphography (MRL) shows satisfactory temporal and spatial resolution. The aim of this study was to assess both the superficial and deep lymphatic system in the upper extremity of healthy subjects, using an MRL protocol. Methods and Results: Ten healthy volunteers underwent an MRL examination, using a three Tesla MRI unit. Water-soluble gadolinium was used as a contrast agent. MRL images were evaluated by an experienced radiologist on image quality, enhancement of veins and lymphatic vessels, and characteristics of the latter. Overall image quality was good to excellent. In all subjects, veins and lymphatic vessels could be distinguished. Superficial and deep lymphatic vessels were seen in 9 out of 10 subjects. Lymphatic vessels with a diameter between 0.9 and 4.3 mm were measured. Both veins and lymphatic vessels showed their characteristic appearance. Enhancement of veins was seen directly after contrast agent injection, which decreased over time. Lymphatic vessel enhancement slowly increased over time. Mean total MRL examination (room) time was 110 minutes (81 minutes scan time). Conclusions: The MRL protocol accurately visualizes both deep and superficial lymphatic vessels showing their characteristic appearances with high spatial resolution, indicating the MRL can be of value in diagnosing and staging peripheral lymphedema.

Background: Of the 1.38 million women who are diagnosed every year with breast cancer worldwide, 21% will develop arm lymphedema. Near-infrared fluorescence lymphatic imaging (NIRFLI) is an effective method for real-time evaluation of the lymphatic system. Reliability studies of the scoring of this NIRFLI are lacking. The aim of this study is to investigate if evaluation of the superficial lymphatic architecture and transport in patients with breast cancer-related lymphedema through NIRFLI can be performed in a reliable way. Methods and Results: The outcome parameters used to assess agreement were the presence of lymphatic transport from the injection sites, of dermal backflow patterns, of efferent lymphatic vessels, and of lymph nodes. The NIRFLI evaluations were scored before and after a break separately by two assessors. Twenty patients with lymphedema of the arm and/or hand were included. After the injection, there was weak to very strong agreement regarding the presence of transport from the injection sites ( K  = 0.459-1.000). The interpretation of the type of dermal backflow pattern varied from weak (WK = 0.452) to very strong agreement (WK = 1.000) between the two assessors. Agreement in the visualization of efferent lymphatic vessels was weak before and after the break ( K  = 0.490 and K  = 0.571) and agreement regarding the presence of lymph nodes was very strong ( K  = 1.000). Conclusion: Overall, there was moderate to strong agreement between the assessors when evaluating the lymphatic architecture and transport through NIRFLI. The study has been registered at clinicaltrials.gov (NCT02609724).

Background: In patients with secondary upper limb lymphedema, positive correlations have been observed between the dermal back flow (DBF) type and visualization of lymph nodes around the clavicle, between the former and the lymph flow pathway type, and between the latter and the visualization of lymph nodes around the clavicle when using single photon-emission computed tomography/computed tomography/lymphoscintigraphy (SPECT-CT LSG). Methods and Results: We analyzed the associations between the visualization of inguinal lymph nodes, the lymph flow pathway type, and the DBF type using SPECT-CT LSG in 81 patients with unilateral secondary lower limb lymphedema by statistical analysis using Fisher's exact test. We revealed that the lymph flow pathways in the lower limb can be classified into nine types because the type in the lower leg is not always equal to the type in the thigh. Associations were observed between the visualization of inguinal lymph nodes and types of DBF ( p  < 0.01), between the types of lymph flow pathway in the thighs and visualization of the inguinal lymph nodes ( p  = 0.02), and between the lymph flow pathway types in the thighs and lower legs ( p  < 0.01). Conclusion: Detriment to the superficial lymph flow pathways in the lower limb appears to usually start from the proximal side, and deep pathways are considered to become dominant from a compensatory perspective as lymphedema severity increases.

The central lymphatic system consists of the thoracic duct, cisterna chyli and the retroperitoneal lymphatics through which lymph and chyle flows. Disorders of the central lymphatic system can for instance lead to leakage (chylothorax), accumulation of fluid (lymphedema) and retrograde flow (protein losing enteropathy). Abnormalities in the central lymphatic system were overlooked for years, followed by lack of diagnostic and therapeutic options. This has changed, as the technique of intranodal contrast injection in inguinal lymph nodes brought renewed interest in the central lymphatic system. In this article, the importance of intranodal contrast injection in diagnosis and treatment of disorders of the central lymphatic system will be presented through 3 clinical cases.

The aim of the study was to assess injection needle positioning for contrast-enhanced MR-lymphangiography (MRL) by ultrasound-guided injection of saline-solution. 80 patients (33 male, mean age 43.1 years) were referred for MRL. The injection needle position was assessed by injection of saline-solution. Consecutive lymph node distension was observed on sonography followed by MRL. Transpedal MRL was performed when no inguinal lymph nodes could be identified. The inguinal lymph node detection rate was recorded. MR-lymphangiograms were assessed regarding primary (i.e. enhancement of draining lymph vessels) and secondary technical success (i.e. lymph vessel enhancement after repositioning of the needle). MRL was considered as clinically successful if enhancement of the central lymphatic system and/or a lymphatic pathologies were observed. For a total of 92 MRLs 177 groins were evaluated sonographically. In 171/177 groins (96.6%) lymph nodes were identified. After needle placement lymph node distension was observed in 171/171 cases (100%) on saline injection. MR-contrast injection demonstrated enhancement of draining lymph vessels in 163/171 cases (95.3%). In 6/171 cases (3.5%) in-bore needle retraction lead to lymphatic enhancement. In one patient [2/171 nodes (1.1%)] no lymphatic enhancement was seen despite repeated needle repositioning. Overall contrast application was technically successful in 169/171 cases (98.8%). In the 6 groins in which no nodes were identifiable, transpedal MRL was successful. So overall 91/92 MRLs (98.9%) were clinically successful. No complications were recorded. Confirmation of the needle position for nodal MRL by sonographically controlled saline injection is a reliable technique with a high success rate of MRL., (© 2022. The Author(s).)

Lymphatic abnormalities encompass a wide range of disorders spanning solitary common cystic lymphatic malformations (LMs) to entities involving multiple organ systems such as lymphangioleiomyomatosis. Many of these disorders are rare, yet some, such as secondary lymphedema from the treatment of malignancy (radiation therapy and/or lymph node dissection), affect millions of patients worldwide. Owing to complex and variable anatomy, the lymphatics are not as well understood as other organ systems. Further complicating this is the variability in the description of lymphatic disease processes and their nomenclature in the medical literature. In recent years, medical imaging has begun to facilitate a deeper understanding of the physiology and pathologic processes that involve the lymphatic system. Radiology is playing an important and growing role in the diagnosis and treatment of many lymphatic conditions. The authors describe both normal and common variant lymphatic anatomy. Various imaging modalities including nuclear medicine lymphoscintigraphy, conventional lymphangiography, and MR lymphangiography used in the diagnosis and treatment of lymphatic disorders are highlighted. The authors discuss imaging many of the common and uncommon lymphatic disorders, including primary LMs described by the International Society for the Study of Vascular Anomalies 2018 classification system (microcystic, mixed, and macrocystic LMs; primary lymphedema). Secondary central lymphatic disorders are also detailed, including secondary lymphedema and chylous leaks, as well as lymphatic disorders not otherwise easily classified. The authors aim to provide the reader with an overview of the anatomy, pathology, imaging findings, and treatment of a wide variety of lymphatic conditions. © RSNA, 2022.

Background: Promotion of hematoma resolution in a timely manner reduces intracerebral hemorrhage (ICH) brain injury induced by toxic blood components and subsequent neuroinflammation. The meningeal lymphatic system is responsible for clearance of macromolecules and pathogenic substances from the central nervous system; however, its role in intraparenchymal hematoma clearance and ICH outcomes is unknown. In the present study, we aimed to understand the contribution of the meningeal lymphatic system to ICH pathologies and to test whether pharmacological enhancement of meningeal lymphatic function promotes hematoma resolution and brain recovery after ICH., Methods: Immunofluorescence of whole-mount meninges was used to measure complexity and coverage level of meningeal lymphatic vasculature following ICH induction. Fluorescent microbeads and PKH-26-labeled erythrocytes were used to evaluate drainage function of the meningeal lymphatic system. Visudyne treatment, deep cervical lymph node ligation, and VEGF (vascular endothelial growth factor)-C injection were performed to manipulate meningeal lymphatic function. Neurobehavioral performance and hematoma volume were assayed by the cylinder test and histological measurements. Iron deposition, residual erythrocytes, neuronal loss, and astrogliosis were assessed by immunohistochemistry and antibody-based fluorescence staining., Results: Meningeal lymphangiogenesis and enhanced lymphatic drainage occurred during the late phase of ICH. Ablation and blockage of meningeal lymphatic vessels impeded hematoma clearance, whereas pharmacological enhancement of their function reduced hematoma volume, improved behavioral performance, and reduced brain residual erythrocytes, iron deposition, neuronal loss, and astroglial activation., Conclusions: Early enhancement of meningeal lymphatic function is beneficial for ICH recovery. Targeting the meningeal lymphatic system is therefore a potential therapeutic approach for treating ICH.

The lymphatic system is a complicated system consisting of the lymphatic vessels and lymph nodes draining the extracellular fluid containing cellular debris, excess water and toxins to the circulatory system. The lymph nodes serve as a filter, thus, when the lymph fluid returns to the heart, it is completely sterile. In addition, the lymphatic system includes the mucosa-associated lymphoid tissue, such as tonsils, adenoids, Peyers patches in the small bowel and even the appendix. Taking advantage of the drainage system of the lymphatics, cancer cells enter the lymphatic vessels and then the lymph nodes. In general, the lymph nodes may serve as a gateway in the majority of cases in early cancer. Occasionally, the cancer cells may enter the blood vessels. This review article emphasizes the structural integrity of the lymphatic system through which cancer cells may spread. Using melanoma and breast cancer sentinel lymph node model systems, the spread of early cancer through the lymphatic system is progressive in a majority of cases. The lymphatic systems of the internal organs are much more complicated and difficult to study. Knowledge from melanoma and breast cancer spread to the sentinel lymph node may establish the basic principles of cancer metastasis. The goal of this review article is to emphasize the complexity of the lymphatic system. To date, the molecular mechanisms of cancer spread from the cancer microenvironment to the sentinel lymph node and distant sites are still poorly understood and their elucidation should take major priority in cancer metastasis research., (© 2021. The Author(s).)

Cancer metastasis is the process by which primary cancer cells invade through the lymphatic or blood vessels to distant sites. The molecular mechanisms by which cancer cells spread either through the lymphatic versus blood vessels or both are not well established. Two major developments have helped us to understand the process more clearly. First, the development of the sentinel lymph node (SLN) concept which is well established in melanoma and breast cancer. The SLN is the first lymph node in the draining nodal basin to receive cancer cells. Patients with a negative SLN biopsy show a significantly lower incidence of distant metastasis, suggesting that the SLN may be the major gateway for cancer metastasis in these cancer types. Second, the discovery and characterization of several biomarkers including VEGF-C, LYVE-1, Podoplanin and Prox-1 have opened new vistas in the understanding of the induction of lymphangiogenesis by cancer cells. Cancer cells must complete multiple steps to invade the lymphatic system, some of which may be enabled by the evolution of new traits during cancer progression. Thus, cancer cells may spread initially through the main gateway of the SLN, from which evolving cancer clones can invade the blood vessels to distant sites. Cancer cells may also enter the blood vessels directly, bypassing the SLN to establish distant metastases. Future studies need to pinpoint the molecules that are used by cancer cells at different stages of metastasis via different routes so that specific therapies can be targeted against these molecules, with the goal of stopping or preventing cancer metastasis., (© 2021. The Author(s).)

In the present study, we aimed to identify the normal hindlimb lymphatic systems in rats and compare them with the detours after lymphatic flow blockage. The lymphatic systems of the hindlimbs of normal rats were investigated via lymphography using a near-infrared fluorescence imaging system. The lymphatic vessels were stained using Evans Blue. The lymphatic flow was blocked through lymphatic vessel ligation combined with inguinal and popliteal lymph node dissection. Detours that appeared after 30 days were visualized using lymphography and immunostaining with anti-podoplanin antibodies. Three main results were obtained in the present study. First, the deep medial system, the superficial medial system, a connection between the superficial and deep medial lymphatic systems, and the superficial lateral system, were elucidated. Second, three types of detours, namely the detour of the lateral abdomen, the detour to the lymphatic vessel near the midline of the abdomen, and the detour to the contralateral inguinal lymph node, were identified after lymphatic flow blockage. Lastly, detours were located in the fatty layer above the panniculus carnosus muscle and their lumina were wide. The histology suggested that the detour was a pre-collecting lymphatic vessel. Lymphatic routes in the rat hindlimbs after lymphatic flow blockage were different from those of the normal rat lymphatic system. It was suggested that the detour is a pre-collecting lymphatic vessel and that encouraging its development may be a new method of simple lymphatic drainage., Competing Interests: The authors have declared that no competing interests exist.

Because diagnostic tools for discriminating between hepatocellular carcinoma (HCC) and advanced cirrhosis are poor, HCC is often detected in a stage where transarterial chemoembolization (TACE) is the best treatment option, even though it provides a poor survival gain. Despite having been used worldwide for several decades, TACE still has many limitations. First, there is a vast heterogeneity in the cellular composition and metabolism of HCCs as well as in the patient population, which renders it difficult to identify patients who would benefit from TACE. Often the delivered drug does not penetrate sufficiently selectively and deeply into the tumour and the drug delivery system is not releasing the drug at an optimal clinical rate. In addition, therapeutic effectiveness is limited by the crosstalk between the tumour cells and components of the cirrhotic tumour microenvironment. To improve this widely used treatment of one of our most common and deadly cancers, we need to better understand the complex interactions between drug delivery, local pharmacology, tumour targeting mechanisms, liver pathophysiology, patient and tumour heterogeneity, and resistance mechanisms. This review provides a novel and important overview of clinical data and discusses the role of the tumour microenvironment and lymphatic system in the cirrhotic liver, its potential response to TACE, and current and possible novel DDSs for locoregional treatment.

Cholangiocarcinoma (CCA), or cancer of bile duct epithelial cells, is a very aggressive malignancy characterized by early lymphangiogenesis in the tumor microenvironment (TME) and lymph node (LN) metastasis which correlate with adverse patient outcome. However, the specific roles of lymphatic endothelial cells (LECs) that promote LN metastasis remains unexplored. Here we aimed to identify the dynamic molecular crosstalk between LECs and CCA cells that activate tumor-promoting pathways and enhances lymphangiogenic mechanisms. Our studies show that inflamed LECs produced high levels of chemokine CXCL5 that signals through its receptor CXCR2 on CCA cells. The CXCR2-CXCL5 signaling axis in turn activates EMT (epithelial-mesenchymal transition) inducing MMP (matrix metalloproteinase) genes such as GLI, PTCHD, and MMP2 in CCA cells that promote CCA migration and invasion. Further, rate of mitochondrial respiration and glycolysis of CCA cells was significantly upregulated by inflamed LECs and CXCL5 activation, indicating metabolic reprogramming. CXCL5 also induced lactate production, glucose uptake, and mitoROS. CXCL5 also induced LEC tube formation and increased metabolic gene expression in LECs. In vivo studies using CCA orthotopic models confirmed several of these mechanisms. Our data points to a key finding that LECs upregulate critical tumor-promoting pathways in CCA via CXCR2-CXCL5 axis, which further augments CCA metastasis.

M3258 is the first selective inhibitor of the immunoproteasome subunit LMP7 (Large multifunctional protease 7) in early clinical development with the potential to improve therapeutic utility in patients of multiple myeloma (MM) or other hematological malignancies. Safety pharmacology studies with M3258 did not reveal any functional impairments of the cardiovascular system in several in vitro tests employing human cardiomyocytes and cardiac ion channels (including hERG), guinea pig heart refractory period and force contraction, and rat aortic contraction as well as in cardiovascular function tests in dogs. Following single dose M3258 administration to rats, no changes were observed on respiratory function by using whole body plethysmography, nor did it change (neuro)behavioral parameters in a battery of tests. Based on pivotal 4-week toxicity studies with daily oral dosing of M3258, the identified key target organs of toxicity were limited to the lympho-hematopoietic system in rats and dogs, and to the intestine with its local lymphoid tissues in dogs only. Importantly, the stomach, nervous system, heart, lungs, and kidneys, that may be part of clinically relevant toxicities as reported for pan-proteasome inhibitors, were spared with M3258. Therefore, it is anticipated that by targeting highly selective and potent inhibition of LMP7, the resulting favorable safety profile of M3258 together with the maintained potent anti-tumor activity as previously reported in mouse MM xenograft models, may translate into an improved benefit-risk profile in MM patients., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

DHX15 is a downstream substrate for Akt1, which is involved in key cellular processes affecting vascular biology. Here, we explored the vascular regulatory function of DHX15. Homozygous DHX15 gene deficiency was lethal in mouse and zebrafish embryos. DHX15 -/- zebrafish also showed downregulation of VEGF-C and reduced formation of lymphatic structures during development. DHX15 +/- mice depicted lower vascular density and impaired lymphatic function postnatally. RNAseq and proteome analysis of DHX15 silenced endothelial cells revealed differential expression of genes involved in the metabolism of ATP biosynthesis. The validation of these results demonstrated a lower activity of the Complex I in the mitochondrial membrane of endothelial cells, resulting in lower intracellular ATP production and lower oxygen consumption. After injection of syngeneic LLC1 tumor cells, DHX15 +/- mice showed partially inhibited primary tumor growth and reduced lung metastasis. Our results revealed an important role of DHX15 in vascular physiology and pave a new way to explore its potential use as a therapeutical target for metastasis treatment., (© 2021. The Author(s).)

Here we describe various techniques for visualization of the lymphatic vasculature, particularly in the heart. Addressing macro-, microscopic, and molecular levels of lymphatic organization, we give examples of how to explore the roles of specific antigens/markers expressed in lymphatic vessels and their extracellular matrix as structural and functional elements involved in various biological functions of lymphatics. Some obstacles and technical challenges related to lymphatic visualization are also discussed., (Copyright © 2020. Published by Elsevier Inc.)

Imaging of the lymphatic vasculature has gained great attention in various fields, not only because lymphatic vessels act as a key draining system in the body, but also for their implication in autoimmune diseases, organ transplant, inflammation and cancer. Thus, neolymphangiogenesis, or the generation of new lymphatics, is typically an early event in the development of multiple tumor types, particularly in aggressive ones such as malignant melanoma. Still, the understanding of how lymphatic endothelial cells get activated at distal (pre)metastatic niches and their impact on therapy is still unclear. Addressing these questions is of particular interest in the case of immune modulators, because endothelial cells may favor or halt inflammatory processes depending on the cellular context. Therefore, there is great interest in visualizing the lymphatic vasculature in vivo. Here, we review imaging tools and mouse models used to analyze the lymphatic vasculature during tumor progression. We also discuss therapeutic approaches based on nanomedicines to target the lymphatic system and the potential use of extracellular vesicles to track and target sentinel lymph nodes. Finally, we summarize main pre-clinical models developed to visualize the lymphatic vasculature in vivo, discussing their applications with a particular focus in metastatic melanoma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Vascular endothelial growth factor receptors (VEGFRs) are part of the evolutionarily conserved VEGF signalling pathways that regulate the development and maintenance of the body's cardiovascular and lymphovascular systems. VEGFR3, encoded by the FLT4 gene, has an indispensable and well-characterized function in development and establishment of the lymphatic system. Autosomal dominant VEGFR3 mutations, that prevent the receptor functioning as a homodimer, cause one of the major forms of hereditary primary lymphoedema; Milroy disease. Recently, we and others have shown that FLT4 variants, distinct to those observed in Milroy disease cases, predispose individuals to Tetralogy of Fallot, the most common cyanotic congenital heart disease, demonstrating a novel function for VEGFR3 in early cardiac development. Here, we examine the familiar and emerging roles of VEGFR3 in the development of both lymphovascular and cardiovascular systems, respectively, compare how distinct genetic variants in FLT4 lead to two disparate human conditions, and highlight the research still required to fully understand this multifaceted receptor., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Lymphatic abnormalities play a role in effusions in individuals with a Fontan circulation. Recent results using near-infrared fluorescence imaging disclosed an increased contraction frequency of lymphatic vessels in Fontan patients compared to healthy controls. It is proposed that the elevated lymphatic pumping seen in the Fontan patients is necessary to maintain habitual interstitial fluid balance. Hyperthermia has previously been used as a tool for lymphatic stress test. By increasing fluid filtration in the capillary bed, the lymphatic workload and contraction frequency are increased accordingly. Using near-infrared fluorescence imaging, the lymphatic functional reserve capacity in Fontan patients were explored with a lymphatic stress test., Methods: Fontan patients (n = 33) were compared to a group of 15 healthy individuals of equal age, weight, and gender. The function of the superficial lymphatic vessels in the lower leg during rest and after inducing hyperthermia was investigated, using near-infrared fluorescence imaging., Results: Baseline values in the Fontan patients showed a 57% higher contraction frequency compared to the healthy controls (0.4 ± 0.3 min -1 vs. 0.3 ± 0.2 min -1 , p = 0.0445). After inducing stress on the lymphatic vessels with hyperthermia the ability to increase contraction frequency was decreased in the Fontan patients compared to the controls (0.6 ± 0.5 min -1 vs. 1.2 ± 0.8 min -1 , p = 0.0102)., Conclusions: Fontan patients had a higher lymphatic contraction frequency during normal circumstances. In the Fontan patients, the hyperthermia response is dampened indicating that the functional lymphatic reserve capacity is depressed. This diminished reserve capacity could be part of the explanation as to why some Fontan patients develop late-onset lymphatic complications., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Innate immune cellular effectors are actively consumed during systemic inflammation, but the systemic traffic and the mechanisms that support their replenishment remain unknown. Here, we demonstrate that acute systemic inflammation induces the emergent activation of a previously unrecognized system of rapid migration of granulocyte-macrophage progenitors and committed macrophage-dendritic progenitors, but not other progenitors or stem cells, from bone marrow (BM) to regional lymphatic capillaries. The progenitor traffic to the systemic lymphatic circulation is mediated by Ccl19/Ccr7 and is NF-κB independent, Traf6/IκB-kinase/SNAP23 activation dependent, and is responsible for the secretion of pre-stored Ccl19 by a subpopulation of CD205 + /CD172a + conventional dendritic cells type 2 and upregulation of BM myeloid progenitor Ccr7 signaling. Mature myeloid Traf6 signaling is anti-inflammatory and necessary for lymph node myeloid cell development. This report unveils the existence and the mechanistic basis of a very early direct traffic of myeloid progenitors from BM to lymphatics during inflammation., Competing Interests: JS, SH, SK, JS, JF, AW, PR, YR, LC, HG, HG, SL, IM, JS, DS, JC No competing interests declared

Background and Aims: Alteration to both the structures and functions of mesenteric lymphatic vessels is a typical hallmark of Crohn's disease [CD]. Dysfunctional lymphatics was observed in patients with both CD and experimental colitis, suggesting mesenteric lymphatics could be potential therapeutic targets. This study aimed to develop a nano-delivery system which can enhance drug delivery in mesenteric lymphatic tissue [MLT] and evaluate the therapeutic effects in Crohn's colitis., Methods: We designed a mesoporous silica nanoparticle [MSN] conjugated with long-chain fatty acid [LMSN] and covered with enteric coating [ELMSN] which can be specifically transported via the mesenteric lymphatic system. The therapeutic efficacy of laquinimod-loaded nanoparticles [LAQ@ELMSN] was evaluated in the well-established interleukin [IL]-10-/- spontaneous experimental colitis., Results: ELMSNs induced sustainable drug release that markedly increased drug concentration in MLT. In experimental colitis, the lymphatics-targeting drug delivery system suppressed lymphangitis and promoted lymphatic drainage. The downregulation of pro-inflammatory cytokines and the downstream NF-κB-related proteins efficiently inhibited lymphangiogenesis and restored tight junctions of mesenteric lymphatic vessels [MLVs]. LAQ@ELMSN showed a superior therapeutic effect in ameliorating intestinal inflammation compared with free drug administration. Alteration of gut microbiota and metabolites in experimental colitis was also reversed by LAQ@ELMSN., Conclusion: Our study demonstrates a convenient, orally administered drug delivery system which enhances drug release in MLT. The results confirm the contribution of the mesenteric lymphatic system to the pathogenesis of gut inflammation and shed light on the application of lymphatics-targeting drug delivery therapy as a potential therapeutic strategy for CD treatment., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Diminished lymphatic function and abnormal morphology are common in chronic inflammatory diseases. Recent studies are investigating whether it is possible to target chronic inflammation by promoting resolution of inflammation, in order to enhance lymphatic function and attenuate disease. Resolution of inflammation is an active process regulated by bioactive lipids known as specialized pro-resolving mediators (SPMs). SPMs can modulate leukocyte migration and function, alter cytokine/chemokine release, modify autophagy, among other immune-related activities. Here, we summarize the role of the lymphatics in resolution of inflammation and lymphatic impairment in chronic inflammatory diseases. Furthermore, we discuss the current literature describing the connection between SPMs and the lymphatics, and the possibility of targeting the lymphatics with innovative SPM therapy to promote resolution of inflammation and mitigate disease.