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"Lymphatic System - physiology"
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Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation
PIEZO1 is a cation channel that is activated by mechanical forces such as fluid shear stress or membrane stretch. PIEZO1 loss-of-function mutations in patients are associated with congenital lymphedema with pleural effusion. However, the mechanistic link between PIEZO1 function and the development or function of the lymphatic system is currently unknown. Here, we analyzed two mouse lines lacking PIEZO1 in endothelial cells (via Tie2Cre or Lyve1Cre) and found that they exhibited pleural effusion and died postnatally. Strikingly, the number of lymphatic valves was dramatically reduced in these mice. Lymphatic valves are essential for ensuring proper circulation of lymph. Mechanical forces have been implicated in the development of lymphatic vasculature and valve formation, but the identity of mechanosensors involved is unknown. Expression of FOXC2 and NFATc1, transcription factors known to be required for lymphatic valve development, appeared normal in Tie2Cre;Piezo1cKO
mice. However, the process of protrusion in the valve leaflets, which is associated with collective cell migration, actin polymerization, and remodeling of cell–cell junctions, was impaired in Tie2Cre;Piezo1cKO
mice. Consistent with these genetic findings, activation of PIEZO1 by Yoda1 in cultured lymphatic endothelial cells induced active remodeling of actomyosin and VE-cadherin⁺ cell–cell adhesion sites. Our analysis provides evidence that mechanically activated ion channel PIEZO1 is a key regulator of lymphatic valve formation.
Journal Article
Understanding the functions and relationships of the glymphatic system and meningeal lymphatics
Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems.
Journal Article
The lymphatic vasculature in disease
Blood vessels form a closed circulatory system, whereas lymphatic vessels form a one-way conduit for tissue fluid and leukocytes. In most vertebrates, the main function of lymphatic vessels is to collect excess protein-rich fluid that has extravasated from blood vessels and transport it back into the blood circulation. Lymphatic vessels have an important immune surveillance function, as they import various antigens and activated antigen-presenting cells into the lymph nodes and export immune effector cells and humoral response factors into the blood circulation. Defects in lymphatic function can lead to lymph accumulation in tissues, dampened immune responses, connective tissue and fat accumulation, and tissue swelling known as lymphedema. This review highlights the most recent developments in lymphatic biology and how the lymphatic system contributes to the pathogenesis of various diseases involving immune and inflammatory responses and its role in disseminating tumor cells.
Journal Article
Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice
Cerebrospinal fluid (CSF) has been commonly accepted to drain through arachnoid projections from the subarachnoid space to the dural venous sinuses. However, a lymphatic component to CSF outflow has long been known. Here, we utilize lymphatic-reporter mice and high-resolution stereomicroscopy to characterize the anatomical routes and dynamics of outflow of CSF. After infusion into a lateral ventricle, tracers spread into the paravascular spaces of the pia mater and cortex of the brain. Tracers also rapidly reach lymph nodes using perineural routes through foramina in the skull. Using noninvasive imaging techniques that can quantify the transport of tracers to the blood and lymph nodes, we find that lymphatic vessels are the major outflow pathway for both large and small molecular tracers in mice. A significant decline in CSF lymphatic outflow is found in aged compared to young mice, suggesting that the lymphatic system may represent a target for age-associated neurological conditions.
It is believed that the bulk of cerebrospinal fluid (CSF) drains through arachnoid projections from the subarachnoid space to the dural venous sinuses. Here the authors show that the major outflow pathway for CSF in mice are lymphatic vessels and that this drainage decreases as the mice age.
Journal Article
Cerebrospinal fluid tracer efflux to parasagittal dura in humans
The mechanisms behind molecular transport from cerebrospinal fluid to dural lymphatic vessels remain unknown. This study utilized magnetic resonance imaging along with cerebrospinal fluid tracer to visualize clearance pathways to human dural lymphatics in vivo. In 18 subjects with suspicion of various types of cerebrospinal fluid disorders, 3D T2-Fluid Attenuated Inversion Recovery, T1-black-blood, and T1 gradient echo acquisitions were obtained prior to intrathecal administration of the contrast agent gadobutrol (0.5 ml, 1 mmol/ml), serving as a cerebrospinal fluid tracer. Propagation of tracer was followed with T1 sequences at 3, 6, 24 and 48 h after the injection. The tracer escaped from cerebrospinal fluid into parasagittal dura along the superior sagittal sinus at areas nearby entry of cortical cerebral veins. The findings demonstrate that trans-arachnoid molecular passage does occur and suggest that parasagittal dura may serve as a bridging link between human brain and dural lymphatic vessels.
Mechanisms behind molecular transport from cerebrospinal fluid to dural lymphatic vessels remain unknown. This study demonstrates that trans-arachnoid molecular passage does occur and suggests that parasagittal dura may serve as a bridging link between human brain and dural lymphatic vessels.
Journal Article
Distinct origins and molecular mechanisms contribute to lymphatic formation during cardiac growth and regeneration
In recent years, there has been increasing interest in the role of lymphatics in organ repair and regeneration, due to their importance in immune surveillance and fluid homeostasis. Experimental approaches aimed at boosting lymphangiogenesis following myocardial infarction in mice, were shown to promote healing of the heart. Yet, the mechanisms governing cardiac lymphatic growth remain unclear. Here, we identify two distinct lymphatic populations in the hearts of zebrafish and mouse, one that forms through sprouting lymphangiogenesis, and the other by coalescence of isolated lymphatic cells. By tracing the development of each subset, we reveal diverse cellular origins and differential response to signaling cues. Finally, we show that lymphatic vessels are required for cardiac regeneration in zebrafish as mutants lacking lymphatics display severely impaired regeneration capabilities. Overall, our results provide novel insight into the mechanisms underlying lymphatic formation during development and regeneration, opening new avenues for interventions targeting specific lymphatic populations.
Journal Article
Anatomical mapping and quantitative functional analysis of lower limb lymphatic flow in normal cynomolgus monkeys using indocyanine green lymphography
The lymphatic system is essential for fluid balance and immune regulation, but its anatomy and function in translational models remain insufficiently defined. Indocyanine green (ICG) near-infrared fluorescence lymphography enables real-time visualization of superficial lymphatics, yet baseline functional data in non-human primates are lacking. Cynomolgus monkeys closely resemble humans and represent a relevant model for lymphatic research. This study established baseline drainage patterns and functional contractility metrics of the lower limb lymphatic system.
Five healthy female cynomolgus monkeys were studied, with a total of 10 lower limbs evaluated. Lymphatic drainage was mapped using 11 intradermal injection sites and near-infrared fluorescence imaging. For functional analysis, ICG was injected into the anteromedial and anterolateral regions, which consistently exhibited clear lymphatic channels suitable for signal extraction. Fluorescence signals were analyzed using peak-valley and wavelet methods to quantify contraction metrics. Functional parameters were assessed at multiple time points for temporal stability. Comparisons were performed within each pathway, and pooled values were used for paired comparisons between the medial and lateral pathways.
Anatomical mapping revealed four major drainage groups. The anteromedial, posteromedial, and anterolateral regions drained predominantly to the inguinal lymph node, whereas posterolateral regions drained mainly to the popliteal lymph node. Functionally, lymphatic contractions remained temporally stable, and medial pathways exhibited significantly higher peak frequency, wavelet mean frequency, amplitude, and wavelet amplitude compared with that of the lateral pathways, indicating more frequent and stronger contractions. Lateral pathways showed slightly greater variability in contraction rhythm.
This study provides the first integrated anatomical and functional characterization of lower limb lymphatics in cynomolgus monkeys. The findings establish baseline parameters that may guide comparative analyses, support pathway-specific investigations, and serve as baseline data for future studies of lymphatic dysfunction and disease modeling in non-human primates.
Journal Article
Lymphatic transport of exosomes as a rapid route of information dissemination to the lymph node
It is well documented that cells secrete exosomes, which can transfer biomolecules that impact recipient cells’ functionality in a variety of physiologic and disease processes. The role of lymphatic drainage and transport of exosomes is as yet unknown, although the lymphatics play critical roles in immunity and exosomes are in the ideal size-range for lymphatic transport. Through
in vivo
near-infrared (NIR) imaging we have shown that exosomes are rapidly transported within minutes from the periphery to the lymph node by lymphatics. Using an
in vitro
model of lymphatic uptake, we have shown that lymphatic endothelial cells actively enhanced lymphatic uptake and transport of exosomes to the luminal side of the vessel. Furthermore, we have demonstrated a differential distribution of exosomes in the draining lymph nodes that is dependent on the lymphatic flow. Lastly, through endpoint analysis of cellular distribution of exosomes in the node, we identified macrophages and B-cells as key players in exosome uptake. Together these results suggest that exosome transfer by lymphatic flow from the periphery to the lymph node could provide a mechanism for rapid exchange of infection-specific information that precedes the arrival of migrating cells, thus priming the node for a more effective immune response.
Journal Article
Upper limb lymphatic mapping and quantitative functional analysis in normal cynomolgus monkeys using indocyanine green near-infrared fluorescence lymphography
The lymphatic system supports immune transport and fluid balance, and disruption of upper-limb lymphatic drainage can contribute to chronic lymphedema. However, baseline information on normal upper-limb lymphatic pathways and pumping function remains limited in physiologically relevant large animal models. In this study, indocyanine green near-infrared fluorescence lymphography was used to map superficial lymphatic drainage and assess lymphatic contractility in 10 upper limbs of five healthy cynomolgus monkeys. Superficial collectors consistently converged toward the axillary lymph node through pathways aligned with the cephalic and basilic veins, and no major superficial drainage was visualized on the lateral surface of the upper limb. Volar lymphatic flow merged with radial or ulnar pathways without forming an independent route. Quantitative analysis demonstrated measurable lymphatic pumping activity, and contractility measures remained stable at 5, 10, and 15 min after injection. Transit time measurements showed substantial interindividual variability. These findings provide baseline anatomical and functional reference data for superficial upper-limb lymphatics in cynomolgus monkeys and support fluorescence lymphography as a practical approach for quantitative assessment in nonhuman primate upper limbs.
Journal Article