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Lymphangiogenesis in Development and Disease—Taking a Fresh Look at the Forming Lymphatics

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Special Issue Information
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Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 May 2021) | Viewed by 25735

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Special Issue Editors

Adj. Prof. Dr. Sinem Karaman

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Guest Editor

University of Helsinki and Wihuri Research Institute, Helsinki, Finland
Interests: obesity, VEGFR signaling; lymphatic vessels; blood vessels; inflammation; vascular leakage; intravital imaging

Dr. Maike Frye

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Guest Editor

Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg (UKE), Hamburg, Germany
Interests: lymphatic development; matrix stiffness regulation of endothelial behaviour; endothelial microenvironment; endothelial junctions; endothelial permeability; lymphatic and blood vessel maintenance

Dr. Katarzyna Koltowska

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Guest Editor

Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Interests: lymphatic development; zebrafish; developmental biology; cell fate; cell proliferation and cell migration

Special Issue Information

Dear Colleagues,

For a long time, lymphatic vessels have been considered passive conduits for fluid drainage from the periphery. Owing to new developments in lymphatic endothelial biology and recently established tools, we continue to uncover further details of how lymphatic vessels form and function. Especially in the past two decades, tremendous progress has been made towards elucidating the anatomy and function of the lymphatic system. Improved imaging technologies and the maturation of omics approaches such as single-cell RNA sequencing have rekindled the debate about the origin and extent of coverage of lymphatic vessels. These developments have also led to new concepts of organotypic heterogeneity and organ-specific lymphatic functions. Such new and exciting findings highlight the importance of lymphatic vessels in organ homeostasis and in a variety of diseases, hence making this Special Issue on lymphangiogenesis timely.

Here, we aim to bring together current research studies that cover the new developments and discoveries in lymphatic endothelial cell biology, including findings from omics approaches and new imaging modalities. This Special Issue will focus on both basic biology of lymphangiogenic mechanisms and emerging fields such as lymphatic mechanotransduction and organotypic heterogeneity of lymphatic endothelial cells in development and disease. Therefore, this collection will illustrate how the field is moving forward, featuring the state of the art in lymphatic research.

For this Special Issue, we welcome both original studies and review articles addressing one or several of the above subjects or of the topics mentioned in the keywords listed below.

Adj. Prof. Dr. Sinem Karaman
Dr. Maike Frye
Dr. Katarzyna Koltowska
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

basic mechanisms of lymphatic vessel growth and signalling
models of lymphangiogenesis
organ-specific lymphatic endothelium
lymphatic microenvironment
omics approaches (Single-cell RNAseq, proteomics, metabolomics, lipidomics, etc.)
imaging techniques

Published Papers (5 papers)

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Research

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21 pages, 4036 KiB

Open AccessArticle

Extracellular Hsp90α Promotes Tumor Lymphangiogenesis and Lymph Node Metastasis in Breast Cancer

by Qiaoyun Hou, Shuohua Chen, Qi An, Boya Li, Yan Fu and Yongzhang Luo

Int. J. Mol. Sci. 2021, 22(14), 7747; https://doi.org/10.3390/ijms22147747 - 20 Jul 2021

Cited by 22 | Viewed by 2926

Abstract

Early detection and discovery of new therapeutic targets are urgently needed to improve the breast cancer treatment outcome. Here we conducted an official clinical trial with cross-validation to corroborate human plasma Hsp90α as a novel breast cancer biomarker. Importantly, similar results were noticed in detecting early-stage breast cancer patients. Additionally, levels of plasma Hsp90α in breast cancer patients were gradually elevated as their clinical stages of regional lymph nodes advanced. In orthotopic breast cancer mouse models, administrating with recombinant Hsp90α protein increased both the primary tumor lymphatic vessel density and sentinel lymph node metastasis by 2 and 10 times, respectively. What is more, Hsp90α neutralizing antibody treatment approximately reduced 70% of lymphatic vessel density and 90% of sentinel lymph node metastasis. In the in vitro study, we demonstrated the role of extracellular Hsp90α (eHsp90α) as a pro-lymphangiogenic factor, which significantly enhanced migration and tube formation abilities of lymphatic endothelial cells (LECs). Mechanistically, eHsp90α signaled to the AKT pathway through low-density lipoprotein receptor-related protein 1 (LRP1) to upregulate the expression and secretion of CXCL8 in the lymphangiogenic process. Collectively, this study proves that plasma Hsp90α serves as an auxiliary diagnosis biomarker and eHsp90α as a molecular mediator promoting lymphangiogenesis in breast cancer. Full article

(This article belongs to the Special Issue Lymphangiogenesis in Development and Disease—Taking a Fresh Look at the Forming Lymphatics)

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Review

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16 pages, 2103 KiB

Open AccessReview

Regulation of VEGFR Signalling in Lymphatic Vascular Development and Disease: An Update

by Genevieve A. Secker and Natasha L. Harvey

Int. J. Mol. Sci. 2021, 22(14), 7760; https://doi.org/10.3390/ijms22147760 - 20 Jul 2021

Cited by 38 | Viewed by 5244

Abstract

The importance of lymphatic vessels in a myriad of human diseases is rapidly gaining recognition; lymphatic vessel dysfunction is a feature of disorders including congenital lymphatic anomalies, primary lymphoedema and obesity, while improved lymphatic vessel function increases the efficacy of immunotherapy for cancer and neurological disease and promotes cardiac repair following myocardial infarction. Understanding how the growth and function of lymphatic vessels is precisely regulated therefore stands to inform the development of novel therapeutics applicable to a wide range of human diseases. Lymphatic vascular development is initiated during embryogenesis following establishment of the major blood vessels and the onset of blood flow. Lymphatic endothelial progenitor cells arise from a combination of venous and non-venous sources to generate the initial lymphatic vascular structures in the vertebrate embryo, which are then further ramified and remodelled to elaborate an extensive lymphatic vascular network. Signalling mediated via vascular endothelial growth factor (VEGF) family members and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases is crucial for development of both the blood and lymphatic vascular networks, though distinct components are utilised to different degrees in each vascular compartment. Although much is known about the regulation of VEGFA/VEGFR2 signalling in the blood vasculature, less is understood regarding the mechanisms by which VEGFC/VEGFD/VEGFR3 signalling is regulated during lymphatic vascular development. This review will focus on recent advances in our understanding of the cellular and molecular mechanisms regulating VEGFA-, VEGFC- and VEGFD-mediated signalling via VEGFRs which are important for driving the construction of lymphatic vessels during development and disease. Full article

(This article belongs to the Special Issue Lymphangiogenesis in Development and Disease—Taking a Fresh Look at the Forming Lymphatics)

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31 pages, 3305 KiB

Open AccessReview

The BMP Pathway in Blood Vessel and Lymphatic Vessel Biology

by Ljuba C. Ponomarev, Jakub Ksiazkiewicz, Michael W. Staring, Aernout Luttun and An Zwijsen

Int. J. Mol. Sci. 2021, 22(12), 6364; https://doi.org/10.3390/ijms22126364 - 14 Jun 2021

Cited by 5 | Viewed by 4825

Abstract

Bone morphogenetic proteins (BMPs) were originally identified as the active components in bone extracts that can induce ectopic bone formation. In recent decades, their key role has broadly expanded beyond bone physiology and pathology. Nowadays, the BMP pathway is considered an important player in vascular signaling. Indeed, mutations in genes encoding different components of the BMP pathway cause various severe vascular diseases. Their signaling contributes to the morphological, functional and molecular heterogeneity among endothelial cells in different vessel types such as arteries, veins, lymphatic vessels and capillaries within different organs. The BMP pathway is a remarkably fine-tuned pathway. As a result, its signaling output in the vessel wall critically depends on the cellular context, which includes flow hemodynamics, interplay with other vascular signaling cascades and the interaction of endothelial cells with peri-endothelial cells and the surrounding matrix. In this review, the emerging role of BMP signaling in lymphatic vessel biology will be highlighted within the framework of BMP signaling in the circulatory vasculature. Full article

(This article belongs to the Special Issue Lymphangiogenesis in Development and Disease—Taking a Fresh Look at the Forming Lymphatics)

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33 pages, 1829 KiB

Open AccessReview

In Sickness and in Health: The Immunological Roles of the Lymphatic System

by Louise A. Johnson

Int. J. Mol. Sci. 2021, 22(9), 4458; https://doi.org/10.3390/ijms22094458 - 24 Apr 2021

Cited by 13 | Viewed by 5914

Abstract

The lymphatic system plays crucial roles in immunity far beyond those of simply providing conduits for leukocytes and antigens in lymph fluid. Endothelial cells within this vasculature are distinct and highly specialized to perform roles based upon their location. Afferent lymphatic capillaries have unique intercellular junctions for efficient uptake of fluid and macromolecules, while expressing chemotactic and adhesion molecules that permit selective trafficking of specific immune cell subsets. Moreover, in response to events within peripheral tissue such as inflammation or infection, soluble factors from lymphatic endothelial cells exert “remote control” to modulate leukocyte migration across high endothelial venules from the blood to lymph nodes draining the tissue. These immune hubs are highly organized and perfectly arrayed to survey antigens from peripheral tissue while optimizing encounters between antigen-presenting cells and cognate lymphocytes. Furthermore, subsets of lymphatic endothelial cells exhibit differences in gene expression relating to specific functions and locality within the lymph node, facilitating both innate and acquired immune responses through antigen presentation, lymph node remodeling and regulation of leukocyte entry and exit. This review details the immune cell subsets in afferent and efferent lymph, and explores the mechanisms by which endothelial cells of the lymphatic system regulate such trafficking, for immune surveillance and tolerance during steady-state conditions, and in response to infection, acute and chronic inflammation, and subsequent resolution. Full article

(This article belongs to the Special Issue Lymphangiogenesis in Development and Disease—Taking a Fresh Look at the Forming Lymphatics)

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17 pages, 847 KiB

Open AccessReview

Specialized Pro-Resolving Mediators and the Lymphatic System

by Jamie D. Kraft, Robert Blomgran, Iben Lundgaard, Marianne Quiding-Järbrink, Jonathan S. Bromberg and Emma Börgeson

Int. J. Mol. Sci. 2021, 22(5), 2750; https://doi.org/10.3390/ijms22052750 - 9 Mar 2021

Cited by 9 | Viewed by 5635

Abstract

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. Full article

(This article belongs to the Special Issue Lymphangiogenesis in Development and Disease—Taking a Fresh Look at the Forming Lymphatics)

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