scholarly journals Mechanisms and cell lineages in lymphatic vascular development

Angiogenesis ◽  
2021 ◽  
Author(s):  
Daniyal J. Jafree ◽  
David A. Long ◽  
Peter J. Scambler ◽  
Christiana Ruhrberg
Keyword(s):  
Emerging Technologies ◽  
Vascular Development ◽  
Lymphatic Vessels ◽  
Experimental Techniques ◽  
Knowledge Gaps ◽  
Cellular Mechanisms ◽  
Cell Lineages ◽  
Lymphatic Vasculature ◽  
Lymphatic Development ◽  
Health And Disease

AbstractLymphatic vessels have critical roles in both health and disease and their study is a rapidly evolving area of vascular biology. The consensus on how the first lymphatic vessels arise in the developing embryo has recently shifted. Originally, they were thought to solely derive by sprouting from veins. Since then, several studies have uncovered novel cellular mechanisms and a diversity of contributing cell lineages in the formation of organ lymphatic vasculature. Here, we review the key mechanisms and cell lineages contributing to lymphatic development, discuss the advantages and limitations of experimental techniques used for their study and highlight remaining knowledge gaps that require urgent attention. Emerging technologies should accelerate our understanding of how lymphatic vessels develop normally and how they contribute to disease.

scholarly journals ALK1 signaling regulates early postnatal lymphatic vessel development

Blood ◽  
2010 ◽  
Vol 115 (8) ◽  
pp. 1654-1661 ◽  
Author(s):  
Kyle Niessen ◽  
Gu Zhang ◽  
John Brady Ridgway ◽  
Hao Chen ◽  
Minhong Yan
Keyword(s):  
Endothelial Cells ◽  
Transforming Growth Factor ◽  
Vascular Development ◽  
Lymphatic Vessels ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Lymphatic Endothelial Cells ◽  
Multiple Organs ◽  
Lymphatic Development

Abstract In vertebrates, endothelial cells form 2 hierarchical tubular networks, the blood vessels and the lymphatic vessels. Despite the difference in their structure and function and genetic programs that dictate their morphogenesis, common signaling pathways have been recognized that regulate both vascular systems. ALK1 is a member of the transforming growth factor-β type I family of receptors, and compelling genetic evidence suggests its essential role in regulating blood vascular development. Here we report that ALK1 signaling is intimately involved in lymphatic development. Lymphatic endothelial cells express key components of the ALK1 pathway and respond robustly to ALK1 ligand stimulation in vitro. Blockade of ALK1 signaling results in defective lymphatic development in multiple organs of neonatal mice. We find that ALK1 signaling regulates the differentiation of lymphatic endothelial cells to influence the lymphatic vascular development and remodeling. Furthermore, simultaneous inhibition of ALK1 pathway increases apoptosis in lymphatic vessels caused by blockade of VEGFR3 signaling. Thus, our study reveals a novel aspect of ALK1 signaling in regulating lymphatic development and suggests that targeting ALK1 pathway might provide additional control of lymphangiogenesis in human diseases.

scholarly journals The Roles of Non-Coding RNAs in Tumor-Associated Lymphangiogenesis

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3290
Author(s):  
Khairunnisa’ Md Yusof ◽  
Rozita Rosli ◽  
Maha Abdullah ◽  
Kelly A. Avery-Kiejda
Keyword(s):  
Growth Factor ◽  
Lymphatic Vessels ◽  
Vascular Endothelial ◽  
Lymphatic Circulation ◽  
Tumor Lymphangiogenesis ◽  
Lymphatic Vasculature ◽  
Lymphatic Development ◽  
Non Coding Rnas ◽  
Endothelial Growth Factor ◽  
Regulation Of Growth

Lymphatic vessels are regarded as the ”forgotten” circulation. Despite this, growing evidence has shown significant roles for the lymphatic circulation in normal and pathological conditions in humans, including cancers. The dissemination of tumor cells to other organs is often mediated by lymphatic vessels that serve as a conduit and is often referred to as tumor-associated lymphangiogenesis. Some of the most well-studied lymphangiogenic factors that govern tumor lymphangiogenesis are the vascular endothelial growth factor (VEGF-C/D and VEGFR-2/3), neuroplilin-2 (NRP2), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF), to name a few. However, recent findings have illustrated that non-coding RNAs are significantly involved in regulating gene expression in most biological processes, including lymphangiogenesis. In this review, we focus on the regulation of growth factors and non-coding RNAs (ncRNAs) in the lymphatic development in normal and cancer physiology. Then, we discuss the lymphangiogenic factors that necessitate tumor-associated lymphangiogenesis, with regards to ncRNAs in various types of cancer. Understanding the different roles of ncRNAs in regulating lymphatic vasculature in normal and cancer conditions may pave the way towards the development of ncRNA-based anti-lymphangiogenic therapy.

scholarly journals Calcium Mobilization in Endothelial Cell Functions

2019 ◽  
Vol 20 (18) ◽  
pp. 4525 ◽  
Author(s):  
Antonio Filippini ◽  
Antonella D’Amore ◽  
Alessio D’Alessio
Keyword(s):  
Vascular System ◽  
Lymphatic Vessels ◽  
Basal Membrane ◽  
Cell Junctions ◽  
Cellular Mechanisms ◽  
Cell Functions ◽  
Innermost Layer ◽  
Health And Disease ◽  
Membrane Bound

Endothelial cells (ECs) constitute the innermost layer that lines all blood vessels from the larger arteries and veins to the smallest capillaries, including the lymphatic vessels. Despite the histological classification of endothelium of a simple epithelium and its homogeneous morphological appearance throughout the vascular system, ECs, instead, are extremely heterogeneous both structurally and functionally. The different arrangement of cell junctions between ECs and the local organization of the basal membrane generate different type of endothelium with different permeability features and functions. Continuous, fenestrated and discontinuous endothelia are distributed based on the specific function carried out by the organs. It is thought that a large number ECs functions and their responses to extracellular cues depend on changes in intracellular concentrations of calcium ion ([Ca2+]i). The extremely complex calcium machinery includes plasma membrane bound channels as well as intracellular receptors distributed in distinct cytosolic compartments that act jointly to maintain a physiological [Ca2+]i, which is crucial for triggering many cellular mechanisms. Here, we first survey the overall notions related to intracellular Ca2+ mobilization and later highlight the involvement of this second messenger in crucial ECs functions with the aim at stimulating further investigation that link Ca2+ mobilization to ECs in health and disease.

scholarly journals The Role of Lymphatic Marker Prox-1 in Relation to Brain Tumours

2021 ◽  
Vol 65 (4) ◽  
pp. 72-78
Author(s):  
J. Teleky ◽  
J. Király
Keyword(s):  
Brain Tumours ◽  
Current Knowledge ◽  
Treatment Options ◽  
Lymphatic Vessels ◽  
Homeobox Gene ◽  
Lymphatic Vasculature ◽  
Lymphatic Development ◽  
The Central Nervous System ◽  
The Brain

Abstract The homeobox gene, Prox-1 is a transcription factor essential for lymphatic development (lymphangiogenesis) during embryogenesis. It also performs different functions in various tissues such as: retina, lens, liver, pancreas and the central nervous system. Intense expression of Prox-1 has been demonstrated in the developing spinal cord and brain. In adulthood its expression continues in the hippocampus and cerebellum. In adult tissues the process of lymphatic vasculature formation is accompanied under certain pathological conditions such as inflammation, tissue repair and tumour growth. Prox-1 expression is typical for lymphatic vessels; thus it belongs to one of the most specific and widely used mammalian lymphatic endothelial marker in the detection of lymphangiogenesis and lymphatic vessel invasion in oncogenesis. It has been shown that Prox-1 is involved in cancer development and progression. It’s tumour suppressive and oncogenic properties are proven in several human cancers, including brain tumours. Among all body cancers the brain tumours represent the most feared tumours with very limited treatment options and a poor diagnosis. The aim of this paper was to show the current knowledge of the gene Prox-1 with an emphasis on brain tumours, especially in gliomas.

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 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.

scholarly journals Efficient aortic lymphatic drainage is necessary for atherosclerosis regression induced by ezetimibe

2020 ◽  
Vol 6 (50) ◽  
pp. eabc2697
Author(s):  
Kim Pin Yeo ◽  
Hwee Ying Lim ◽  
Chung Hwee Thiam ◽  
Syaza Hazwany Azhar ◽  
Caris Tan ◽  
...  
Keyword(s):  
Lymphatic Vessels ◽  
Lymphatic Drainage ◽  
Lymphatic Transport ◽  
Atherosclerotic Plaques ◽  
Tissue Fluid ◽  
Atherosclerosis Progression ◽  
Lymphatic Vasculature ◽  
Lesion Regression ◽  
Transport Of Macromolecules

A functional lymphatic vasculature is essential for tissue fluid homeostasis, immunity, and lipid clearance. Although atherosclerosis has been linked to adventitial lymphangiogenesis, the functionality of aortic lymphatic vessels draining the diseased aorta has never been assessed and the role of lymphatic drainage in atherogenesis is not well understood. We develop a method to measure aortic lymphatic transport of macromolecules and show that it is impaired during atherosclerosis progression, whereas it is ameliorated during lesion regression induced by ezetimibe. Disruption of aortic lymph flow by lymphatic ligation promotes adventitial inflammation and development of atherosclerotic plaque in hypercholesterolemic mice and inhibits ezetimibe-induced atherosclerosis regression. Thus, progression of atherosclerotic plaques may result not only from increased entry of atherogenic factors into the arterial wall but also from reduced lymphatic clearance of these factors as a result of aortic lymph stasis. Our findings suggest that promoting lymphatic drainage might be effective for treating atherosclerosis.

The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 1989-1997 ◽  
Author(s):  
Kyle Niessen ◽  
Gu Zhang ◽  
John Brady Ridgway ◽  
Hao Chen ◽  
Ganesh Kolumam ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Lymphatic Vessels ◽  
Mouse Skin ◽  
Notch Signaling Pathway ◽  
Cell Phenotype ◽  
Mural Cell ◽  
Lymphatic Development ◽  
Vessel Development

Abstract The Notch signaling pathway plays a fundamental role during blood vessel development. Notch signaling regulates blood vessel morphogenesis by promoting arterial endothelial differentiation and pro-viding spatial and temporal control over “tip cell” phenotype during angiogenic sprouting. Components of the Notch signaling pathway have emerged as potential regulators of lymphatic development, joining the increasing examples of blood vessel regulators that are also involved in lymphatic development. However, in mammals a role for the Notch signaling pathway during lymphatic development remains to be demonstrated. In this report, we show that blockade of Notch1 and Dll4, with specific function-blocking antibodies, results in defective postnatal lymphatic development in mice. Mechanistically, Notch1-Dll4 blockade is associated with down-regulation of EphrinB2 expression, been shown to be critically involved in VEGFR3/VEGFC signaling, resulting in reduced lymphangiogenic sprouting. In addition, Notch1-Dll4 blockade leads to compromised expression of distinct lymphatic markers and to dilation of collecting lymphatic vessels with reduced and disorganized mural cell coverage. Finally, Dll4-blockade impairs wound closure and severely affects lymphangiogenesis during the wound healing in adult mouse skin. Thus, our study demonstrates for the first time in a mammalian system that Notch1-Dll4 signaling pathway regulates postnatal lymphatic development and pathologic lymphangiogenesis.

scholarly journals Early developmental asymmetries in cell lineage trees in living individuals

2020 ◽  
Author(s):  
Liana Fasching ◽  
Yeongjun Jang ◽  
Simone Tomasi ◽  
Jeremy Schreiner ◽  
Livia Tomasini ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cell Lineage ◽  
Postmortem Brain ◽  
Cell Lineages ◽  
Human Specimen ◽  
Balanced Contributions ◽  
Health And Disease ◽  
Induced Pluripotent ◽  
Lineage Trees ◽  
Early Developmental

AbstractPost-zygotic mosaic mutations can be used to track cell lineages in humans. By using cell cloning and induced pluripotent cell lines, we analyzed early cell lineages in two living individuals (a patient and a control), and a postmortem human specimen. Of ten reconstructed post-zygotic divisions, none resulted in balanced contributions of daughter lineages to tissues. In both living individuals one of two lineages from the first cleavage was dominant across tissues, with 90% frequency in blood. We propose that the efficiency of DNA repair contributes to lineage imbalance. Allocation of lineages in postmortem brain correlated with anterior-posterior axis, associating lineage history with cell fate choices in embryos. Recurrence of germline variants as mosaic suggested that certain loci may be particularly susceptible to mutagenesis. We establish a minimally invasive framework for defining cell lineages in any living individual, which paves the way for studying their relevance in health and disease.

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