scholarly journals MicroRNA-mediated control of developmental lymphangiogenesis

2019 ◽  
Author(s):  
Hyun Min Jung ◽  
Ciara Hu ◽  
Alexandra M. Fister ◽  
Andrew E. Davis ◽  
Daniel Castranova ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Critical Role ◽  
Lymphatic Vessels ◽  
Molecular Regulation ◽  
Small Rna Sequencing ◽  
Positive Role ◽  
Vessel Formation ◽  
Lymphatic Development ◽  
Lymphatic Network ◽  
Post Transcriptional Regulation

ABSTRACTThe post-transcriptional mechanisms contributing to molecular regulation of developmental lymphangiogenesis and lymphatic network assembly are not well understood. Here, we use high throughput small RNA sequencing to identify miR-204, a highly conserved miRNA dramatically enriched in lymphatic vs. blood endothelial cells, and we demonstrate that this miRNA plays a critical role during lymphatic development. Suppressing miR-204 leads to loss of lymphatic vessel formation, while overproducing miR-204 in lymphatic vessels accelerates lymphatic vessel formation, suggesting a positive role during developmental lymphangiogenesis. We also identify the NFATC1 transcription factor as a key conserved target for post-transcriptional regulation by miR-204 during lymphangiogenesis. While miR-204 suppression leads to loss of lymphatics, knocking down its target NFATC1 leads to lymphatic hyperplasia, and the loss of lymphatics in miR-204-deficient animals can be rescued by NFATC1 knockdown. Together, our results highlight a miR-204/NFATC1 molecular regulatory axis required for proper lymphatic development.

scholarly journals MicroRNA-mediated control of developmental lymphangiogenesis

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Hyun Min Jung ◽  
Ciara T Hu ◽  
Alexandra M Fister ◽  
Andrew E Davis ◽  
Daniel Castranova ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Small Rna ◽  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Transcriptional Regulators ◽  
Molecular Regulation ◽  
Small Rna Sequencing ◽  
Positive Role ◽  
Lymphatic Development ◽  
Lymphatic Network

The post-transcriptional mechanisms contributing to molecular regulation of developmental lymphangiogenesis and lymphatic network assembly are not well understood. MicroRNAs are important post-transcriptional regulators during development. Here, we use high throughput small RNA sequencing to identify miR-204, a highly conserved microRNA dramatically enriched in lymphatic vs. blood endothelial cells in human and zebrafish. Suppressing miR-204 leads to loss of lymphatic vessels while endothelial overproduction of miR-204 accelerates lymphatic vessel formation, suggesting a critical positive role for this microRNA during developmental lymphangiogenesis. We also identify the NFATC1 transcription factor as a key miR-204 target in human and zebrafish, and show that NFATC1 suppression leads to lymphatic hyperplasia. The loss of lymphatics caused by miR-204 deficiency can be largely rescued by either endothelial autonomous expression of miR-204 or by suppression of NFATC1. Together, our results highlight a miR-204/NFATC1 molecular regulatory axis required for proper lymphatic development.

Initial Steps Toward Development of a Lumped-Parameter Model of the Lymphatic Network

2013 ◽  
Author(s):  
Samira Jamalian ◽  
Christopher D. Bertram ◽  
James E. Moore
Keyword(s):  
Blood Circulation ◽  
Lymphatic Vessel ◽  
Lymphatic System ◽  
Lymphatic Vessels ◽  
The Body ◽  
Lumped Parameter Model ◽  
Circulation System ◽  
Blood Circulation System ◽  
Lumped Parameter ◽  
Lymphatic Network

One of the primary functions of the lymphatic system is maintaining fluid and protein balance in the body. The system holds this balance by collecting about four liters of fluid every day from the interstitial space and returning it back to the subclavian vein. In contrast to the blood circulation system that relies on the heart for pumping, there is no central pump in the lymphatic system. Thus, the transport of viscous fluid against gravity and pressure difference occurs by recruiting extrinsic and intrinsic pumping mechanisms. Extrinsic pumping is the transport of lymph due to the movements outside the lymphatic vessel such as the pulse in blood vessels, whereas the intrinsic pumping is transport of lymph by contraction of lymphatic muscle cells embedded in the walls of lymphatic vessels. Similar to the veins, the bi-leaflet valves throughout the lymphatic network prevent backflow. Lymphatic valves are biased open and allow for small amounts of back flow before they completely shut.

scholarly journals Tbx1 regulates Vegfr3 and is required for lymphatic vessel development

2010 ◽  
Vol 189 (3) ◽  
pp. 417-424 ◽  
Author(s):  
Li Chen ◽  
Annalisa Mupo ◽  
Tuong Huynh ◽  
Sara Cioffi ◽  
Matthew Woods ◽  
...  
Keyword(s):  
Lymphatic Vessel ◽  
Perinatal Death ◽  
Major Gene ◽  
Critical Role ◽  
Lymphatic Vessels ◽  
Enhancer Element ◽  
Conditional Deletion ◽  
Tumor Lymphangiogenesis ◽  
Vessel Network ◽  
Vessel Development

Lymphatic dysfunction causes several human diseases, and tumor lymphangiogenesis is implicated in cancer spreading. TBX1 is the major gene for DiGeorge syndrome, which is associated with multiple congenital anomalies. Mutation of Tbx1 in mice recapitulates the human disease phenotype. In this study, we use molecular, cellular, and genetic approaches to show, unexpectedly, that Tbx1 plays a critical role in lymphatic vessel development and regulates the expression of Vegfr3, a gene that is essential for lymphangiogenesis. Tbx1 activates Vegfr3 transcription in endothelial cells (ECs) by binding to an enhancer element in the Vegfr3 gene. Conditional deletion of Tbx1 in ECs causes widespread lymphangiogenesis defects in mouse embryos and perinatal death. Using the mesentery as a model tissue, we show that Tbx1 is not required for lymphatic EC differentiation; rather, it is required for the growth and maintenance of lymphatic vessels. Our findings reveal a novel pathway for the development of the lymphatic vessel network.

Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3531-3536 ◽  
Author(s):  
Renhai Cao ◽  
Meit A. Björndahl ◽  
Marta I. Gallego ◽  
Shaohua Chen ◽  
Piotr Religa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Blood Vessels ◽  
Lymphatic Metastasis ◽  
Lymphatic Vessel ◽  
Critical Role ◽  
Lymphatic Vessels ◽  
Specific Marker ◽  
Indirect Mechanism ◽  
Hepatocyte Growth

Hepatocyte growth factor (HGF) has previously been reported to act as a hemangiogenic factor, as well as a mitogenic factor for a variety of tumor cells. Here, we demonstrate that HGF is a lymphangiogenic factor, which may contribute to lymphatic metastasis when overexpressed in tumors. In a mouse corneal lymphangiogenesis model, implantation of HGF induces sprouting and growth of new lymphatic vessel expressing the lymphatic vessel endothelial specific marker hyaluronan receptor-1 (Lyve-1). Unlike blood vessels, the Lyve-1–positive structures consist of blunt-ended vessels of large diameters that generally lack expression of CD31. The growth of HGF-induced lymphatic vessels can be partially blocked by a soluble VEGFR-3, suggesting that HGF may stimulate lymphatic vessel growth through an indirect mechanism. Consistent with this finding, the HGF receptor (c-Met) is only localized on corneal blood vessels but is absent on lymphatic vessels in a mouse corneal assay. In a transgenic mouse model that expresses HGF under the control of the whey acidic protein (WAP) gene promoter, transgenic females develop tumors in the mammary glands after several pregnancies. Interestingly, dilated Lyve-1–positive lymphatic vessels accumulate in the peritumoral area and occasionally penetrate into the tumor tissue. Our findings indicate that HGF may play a critical role in lymphangiogenesis and potentially contribute to lymphatic metastasis.

scholarly journals Live Imaging of Intracranial Lymphatics in the Zebrafish

2020 ◽  
Author(s):  
Daniel Castranova ◽  
Bakary Samasa ◽  
Marina Venero Galanternik ◽  
Hyun Min Jung ◽  
Van N. Pham ◽  
...  
Keyword(s):  
Experimental Analysis ◽  
Immune Cell ◽  
Lymphatic Vessels ◽  
Model Organism ◽  
Live Imaging ◽  
Cell Trafficking ◽  
Lymphatic Development ◽  
Health And Disease ◽  
Lymphatic Network ◽  
The Brain

ABSTRACTRationaleThe recent discovery of meningeal lymphatics in mammals is reshaping our understanding of fluid homeostasis and cellular waste management in the brain, but visualization and experimental analysis of these vessels is challenging in mammals. Although the optical clarity and experimental advantages of zebrafish have made this an essential model organism for studying lymphatic development, the existence of meningeal lymphatics has not yet been reported in this species.ObjectiveExamine the intracranial space of larval, juvenile, and adult zebrafish to determine whether and where intracranial lymphatic vessels are present.Methods and ResultsUsing high-resolution optical imaging of the meninges in living animals, we show that zebrafish possess a meningeal lymphatic network comparable to that found in mammals. We confirm that this network is separate from the blood vascular network and that it drains interstitial fluid from the brain. We document the developmental origins and growth of these vessels into a distinct network separated from the external lymphatics. Finally we show that these vessels contain immune cells and perform live imaging of immune cell trafficking and transmigration in meningeal lymphatics.ConclusionsThis discovery establishes the zebrafish as a important new model for experimental analysis of meningeal lymphatic development, and opens up new avenues for probing meningeal lymphatic function in health and disease.

scholarly journals Investigating lymphangiogenesis in vitro and in vivo using engineered human lymphatic vessel networks

2021 ◽  
Vol 118 (31) ◽  
pp. e2101931118
Author(s):  
Shira Landau ◽  
Abigail Newman ◽  
Shlomit Edri ◽  
Inbal Michael ◽  
Shahar Ben-Shaul ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessel ◽  
Blood Vessels ◽  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cells ◽  
Supporting Cells ◽  
Vessel Formation ◽  
Vessel Networks

The lymphatic system is involved in various biological processes, including fluid transport from the interstitium into the venous circulation, lipid absorption, and immune cell trafficking. Despite its critical role in homeostasis, lymphangiogenesis (lymphatic vessel formation) is less widely studied than its counterpart, angiogenesis (blood vessel formation). Although the incorporation of lymphatic vasculature in engineered tissues or organoids would enable more precise mimicry of native tissue, few studies have focused on creating engineered tissues containing lymphatic vessels. Here, we populated thick collagen sheets with human lymphatic endothelial cells, combined with supporting cells and blood endothelial cells, and examined lymphangiogenesis within the resulting constructs. Our model required just a few days to develop a functional lymphatic vessel network, in contrast to other reported models requiring several weeks. Coculture of lymphatic endothelial cells with the appropriate supporting cells and intact PDGFR-β signaling proved essential for the lymphangiogenesis process. Additionally, subjecting the constructs to cyclic stretch enabled the creation of complex muscle tissue aligned with the lymphatic and blood vessel networks, more precisely biomimicking native tissue. Interestingly, the response of developing lymphatic vessels to tensile forces was different from that of blood vessels; while blood vessels oriented perpendicularly to the stretch direction, lymphatic vessels mostly oriented in parallel to the stretch direction. Implantation of the engineered lymphatic constructs into a mouse abdominal wall muscle resulted in anastomosis between host and implant lymphatic vasculatures, demonstrating the engineered construct's potential functionality in vivo. Overall, this model provides a potential platform for investigating lymphangiogenesis and lymphatic disease mechanisms.

scholarly journals Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1129-1138 ◽  
Author(s):  
Chang Min Yoon ◽  
Bok Sil Hong ◽  
Hyung Geun Moon ◽  
Seyoung Lim ◽  
Pann-Ghill Suh ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Lymphatic Vessel ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Lymphatic Vessels ◽  
Tissue Fluid ◽  
Vessel Formation ◽  
Sphingosine 1 Phosphate

Abstract The lymphatic system plays pivotal roles in mediating tissue fluid homeostasis and immunity, and excessive lymphatic vessel formation is implicated in many pathological conditions, which include inflammation and tumor metastasis. However, the molecular mechanisms that regulate lymphatic vessel formation remain poorly characterized. Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that is implicated in a variety of biologic processes such as inflammatory responses and angiogenesis. Here, we first report that S1P acts as a lymphangiogenic mediator. S1P induced migration, capillary-like tube formation, and intracellular Ca2+ mobilization, but not proliferation, in human lymphatic endothelial cells (HLECs) in vitro. Moreover, a Matrigel plug assay demonstrated that S1P promoted the outgrowth of new lymphatic vessels in vivo. HLECs expressed S1P1 and S1P3, and both RNA interference–mediated down-regulation of S1P1 and an S1P1 antagonist significantly blocked S1P-mediated lymphangiogenesis. Furthermore, pertussis toxin, U73122, and BAPTA-AM efficiently blocked S1P-induced in vitro lymphangiogenesis and intracellular Ca2+ mobilization of HLECs, indicating that S1P promotes lymphangiogenesis by stimulating S1P1/Gi/phospholipase C/Ca2+ signaling pathways. Our results suggest that S1P is the first lymphangiogenic bioactive lipid to be identified, and that S1P and its receptors might serve as new therapeutic targets against inflammatory diseases and lymphatic metastasis in tumors.

Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4649-4656 ◽  
Author(s):  
Tohru Morisada ◽  
Yuichi Oike ◽  
Yoshihiro Yamada ◽  
Takashi Urano ◽  
Masaki Akao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessel ◽  
Matrix Protein ◽  
Lymphatic Vessels ◽  
Vascular Endothelial ◽  
Vessel Formation ◽  
Lymphatic Vasculature ◽  
In Vitro Effects

Abstract Angiopoietin (Ang) signaling plays a role in angiogenesis and remodeling of blood vessels through the receptor tyrosine kinase Tie2, which is expressed on blood vessel endothelial cells (BECs). Recently it has been shown that Ang-2 is crucial for the formation of lymphatic vasculature and that defects in lymphangiogenesis seen in Ang-2 mutant mice are rescued by Ang-1. These findings suggest important roles for Ang signaling in the lymphatic vessel system; however, Ang function in lymphangiogenesis has not been characterized. In this study, we reveal that lymphatic vascular endothelial hyaluronan receptor 1-positive (LYVE-1+) lymphatic endothelial cells (LECs) express Tie2 in both embryonic and adult settings, indicating that Ang signaling occurs in lymphatic vessels. Therefore, we examined whether Ang-1 acts on in vivo lymphatic angiogenesis and in vitro growth of LECs. A chimeric form of Ang-1, cartilage oligomeric matrix protein (COMP)-Ang-1, promotes in vivo lymphatic angiogenesis in mouse cornea. Moreover, we found that COMP-Ang-1 stimulates in vitro colony formation of LECs. These Ang-1-induced in vivo and in vitro effects on LECs were suppressed by soluble Tie2-Fc fusion protein, which acts as an inhibitor by sequestering Ang-1. On the basis of these observations, we propose that Ang signaling regulates lymphatic vessel formation through Tie2. (Blood. 2005;105:4649-4656)

The contribution of K+ channels to human thoracic duct contractility

2014 ◽  
Vol 307 (1) ◽  
pp. H33-H43 ◽  
Author(s):  
Niklas Telinius ◽  
Sukhan Kim ◽  
Hans Pilegaard ◽  
Einar Pahle ◽  
Jørn Nielsen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Smooth Muscle Cells ◽  
Lymphatic Vessel ◽  
Isometric Force ◽  
Mrna Level ◽  
Critical Role ◽  
Lymphatic Vessels ◽  
Muscle Cells ◽  
Resting Membrane Potential

In smooth muscle cells, K+ permeability is high, and this highly influences the resting membrane potential. Lymph propulsion is dependent on phasic contractions generated by smooth muscle cells of lymphatic vessels, and it is likely that K+ channels play a critical role in regulating contractility in this tissue. The aim of this study was to investigate the contribution of distinct K+ channels to human lymphatic vessel contractility. Thoracic ducts were harvested from 43 patients and mounted in a wire myograph for isometric force measurements or membrane potential recordings with an intracellular microelectrode. Using K+ channel blockers and activators, we demonstrate a functional contribution to human lymphatic vessel contractility from all the major classes of K+ channels [ATP-sensitive K+ (KATP), Ca2+-activated K+, inward rectifier K+, and voltage-dependent K+ channels], and this was confirmed at the mRNA level. Contraction amplitude, frequency, and baseline tension were altered depending on which channel was blocked or activated. Microelectrode impalements of lymphatic vessels determined an average resting membrane potential of −43.1 ± 3.7 mV. We observed that membrane potential changes of <5 mV could have large functional effects with contraction frequencies increasing threefold. In general, KATP channels appeared to be constitutively open since incubation with glibenclamide increased contraction frequency in spontaneously active vessels and depolarized and initiated contractions in previously quiescent vessels. The largest change in membrane voltage was observed with the KATP opener pinacidil, which caused 24 ± 3 mV hyperpolarization. We conclude that K+ channels are important modulators of human lymphatic contractility.

scholarly journals Live Imaging of Intracranial Lymphatics in the Zebrafish

2021 ◽  
Vol 128 (1) ◽  
pp. 42-58 ◽  
Author(s):  
Daniel Castranova ◽  
Bakary Samasa ◽  
Marina Venero Galanternik ◽  
Hyun Min Jung ◽  
Van N. Pham ◽  
...  
Keyword(s):  
Experimental Analysis ◽  
Immune Cell ◽  
Lymphatic Vessels ◽  
Model Organism ◽  
Live Imaging ◽  
Cell Trafficking ◽  
Lymphatic Development ◽  
Health And Disease ◽  
Lymphatic Network ◽  
The Brain

Rationale: The recent discovery of meningeal lymphatics in mammals is reshaping our understanding of fluid homeostasis and cellular waste management in the brain, but visualization and experimental analysis of these vessels is challenging in mammals. Although the optical clarity and experimental advantages of zebrafish have made this an essential model organism for studying lymphatic development, the existence of meningeal lymphatics has not yet been reported in this species. Objective: Examine the intracranial space of larval, juvenile, and adult zebrafish to determine whether and where intracranial lymphatic vessels are present. Methods and Results: Using high-resolution optical imaging of the meninges in living animals, we show that zebrafish possess a meningeal lymphatic network comparable to that found in mammals. We confirm that this network is separate from the blood vascular network and that it drains interstitial fluid from the brain. We document the developmental origins and growth of these vessels into a distinct network separated from the external lymphatics. Finally, we show that these vessels contain immune cells and perform live imaging of immune cell trafficking and transmigration in meningeal lymphatics. Conclusions: This discovery establishes the zebrafish as a important new model for experimental analysis of meningeal lymphatic development and opens up new avenues for probing meningeal lymphatic function in health and disease.

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