Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Current Mechanistic Understandings of Lymphedema and Lipedema

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
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 (30 June 2022) | Viewed by 33485

Share This Special Issue

Special Issue Editors

Dr. Joseph M. Rutkowski

E-Mail Website
Guest Editor

Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX 77807, USA
Interests: microcirculation; interstitial fluid mechanics; lymphatics; lymphangiogenesis; metabolism; inflammation
Special Issues, Collections and Topics in MDPI journals

Dr. Rachelle Crescenzi

E-Mail
Guest Editor

Department of Radiology and Radiological Sciences, Vanderbilt University Institute of Imaging Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
Interests: molecular imaging and biophysics; lymphatic disease; lipedema; tissue sodium storage; adiposity; renal and vascular clearance

Special Issue Information

Dear Colleagues,

While the external presentation of lymphedema and lipedema may appear similar, the diagnosis and molecular mechanisms underlying these conditions are quite varied. Lymphedema results from a genetic or acquired lymphatic deficiency, causing fluid accumulation, inflammation, and adipose tissue expansion. The pathological adipose expansion in lipedema, however, arises from an etiology that is yet to be well defined but potentially includes blood microvascular and lymphatic insufficiency, altered extracellular matrix composition, and dysfunctional adipose biology. It will be important to define how these traditionally understudied diseases are similar and yet distinct in order to meet their unique needs in terms of diagnostics and treatment options.

This Special Issue will publish original articles as well as full reviews that cover the current understanding and molecular and physiological mechanisms that are shared between, and importantly, unique to either lymphedema and lipedema. Manuscripts need not cover both pathologies, but rather should present novel findings about early diagnostics and molecular mechanisms defining what we know and the key remaining questions.

Dr. Joseph M. Rutkowski
Dr. Rachelle Crescenzi
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

lymphedema
lipedema
angiogenesis
lymphangiogenesis
vascular malformations
obesity
adipogenesis
extracellular matrix
inflammation
pain

Published Papers (7 papers)

Download All Papers

Research

Jump to: Review

20 pages, 3054 KiB

Open AccessArticle

Low Efficacy of Genetic Tests for the Diagnosis of Primary Lymphedema Prompts Novel Insights into the Underlying Molecular Pathways

by Gabriele Bonetti, Stefano Paolacci, Michele Samaja, Paolo Enrico Maltese, Sandro Michelini, Serena Michelini, Silvia Michelini, Maurizio Ricci, Marina Cestari, Astrit Dautaj, Maria Chiara Medori and Matteo Bertelli

Int. J. Mol. Sci. 2022, 23(13), 7414; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137414 - 03 Jul 2022

Cited by 5 | Viewed by 2737

Abstract

Lymphedema is a chronic inflammatory disorder caused by ineffective fluid uptake by the lymphatic system, with effects mainly on the lower limbs. Lymphedema is either primary, when caused by genetic mutations, or secondary, when it follows injury, infection, or surgery. In this study, we aim to assess to what extent the current genetic tests detect genetic variants of lymphedema, and to identify the major molecular pathways that underlie this rather unknown disease. We recruited 147 individuals with a clinical diagnosis of primary lymphedema and used established genetic tests on their blood or saliva specimens. Only 11 of these were positive, while other probands were either negative (63) or inconclusive (73). The low efficacy of such tests calls for greater insight into the underlying mechanisms to increase accuracy. For this purpose, we built a molecular pathways diagram based on a literature analysis (OMIM, Kegg, PubMed, Scopus) of candidate and diagnostic genes. The PI3K/AKT and the RAS/MAPK pathways emerged as primary candidates responsible for lymphedema diagnosis, while the Rho/ROCK pathway appeared less critical. The results of this study suggest the most important pathways involved in the pathogenesis of lymphedema, and outline the most promising diagnostic and candidate genes to diagnose this disease. Full article

(This article belongs to the Special Issue Current Mechanistic Understandings of Lymphedema and Lipedema)

► Show Figures

Figure 1

23 pages, 3294 KiB

Open AccessArticle

The Kinetics of Lymphatic Dysfunction and Leukocyte Expansion in the Draining Lymph Node during LTB₄ Antagonism in a Mouse Model of Lymphedema

by Matthew T. Cribb, Lauren F. Sestito, Stanley G. Rockson, Mark R. Nicolls, Susan N. Thomas and J. Brandon Dixon

Int. J. Mol. Sci. 2021, 22(9), 4455; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094455 - 24 Apr 2021

Cited by 11 | Viewed by 2964

Abstract

The mechanisms of lymphedema development are not well understood, but emerging evidence highlights the crucial role the immune system plays in driving its progression. It is well known that lymphatic function deteriorates as lymphedema progresses; however, the connection between this progressive loss of function and the immune-driven changes that characterize the disease has not been well established. In this study, we assess changes in leukocyte populations in lymph nodes within the lymphatic drainage basin of the tissue injury site (draining lymph nodes, dLNs) using a mouse tail model of lymphedema in which a pair of draining collecting vessels are left intact. We additionally quantify lymphatic pump function using established near infrared (NIR) lymphatic imaging methods and lymph-draining nanoparticles (NPs) synthesized and employed by our team for lymphatic tissue drug delivery applications to measure lymphatic transport to and resulting NP accumulation within dLNs associated with swelling following surgery. When applied to assess the effects of the anti-inflammatory drug bestatin, which has been previously shown to be a possible treatment for lymphedema, we find lymph-draining NP accumulation within dLNs and lymphatic function to increase as lymphedema progresses, but no significant effect on leukocyte populations in dLNs or tail swelling. These results suggest that ameliorating this loss of lymphatic function is not sufficient to reverse swelling in this surgically induced disease model that better recapitulates the extent of lymphatic injury seen in human lymphedema. It also suggests that loss of lymphatic function during lymphedema may be driven by immune-mediated mechanisms coordinated in dLNs. Our work indicates that addressing both lymphatic vessel dysfunction and immune cell expansion within dLNs may be required to prevent or reverse lymphedema when partial lymphatic function is sustained. Full article

(This article belongs to the Special Issue Current Mechanistic Understandings of Lymphedema and Lipedema)

► Show Figures

Figure 1

14 pages, 2367 KiB

Open AccessArticle

A Distinct Cytokine Profile and Stromal Vascular Fraction Metabolic Status without Significant Changes in the Lipid Composition Characterizes Lipedema

by Stefan Wolf, Jeremy W. Deuel, Maija Hollmén, Gunther Felmerer, Bong-Sung Kim, Mauro Vasella, Lisanne Grünherz, Pietro Giovanoli, Nicole Lindenblatt and Epameinondas Gousopoulos

Int. J. Mol. Sci. 2021, 22(7), 3313; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073313 - 24 Mar 2021

Cited by 18 | Viewed by 4369

Abstract

Lipedema is an adipose tissue disorder characterized by the disproportionate increase of subcutaneous fat tissue in the lower and/or upper extremities. The underlying pathomechanism remains unclear and no molecular biomarkers to distinguish the disease exist, leading to a large number of undiagnosed and misdiagnosed patients. To unravel the distinct molecular characteristic of lipedema we performed lipidomic analysis of the adipose tissue and serum of lipedema versus anatomically- and body mass index (BMI)-matched control patients. Both tissue groups showed no significant changes regarding lipid composition. As hyperplastic adipose tissue represents low-grade inflammation, the potential systemic effects on circulating cytokines were evaluated in lipedema and control patients using the Multiplex immunoassay system. Interestingly, increased systemic levels of interleukin 11 (p = 0.03), interleukin 28A (p = 0.04) and interleukin 29 (p = 0.04) were observed. As cytokines can influence metabolic activity, the metabolic phenotype of the stromal vascular fraction was examined, revealing significantly increased mitochondrial respiration in lipedema. In conclusion, despite sharing a comparable lipid profile with healthy adipose tissue, lipedema is characterized by a distinct systemic cytokine profile and metabolic activity of the stromal vascular fraction. Full article

(This article belongs to the Special Issue Current Mechanistic Understandings of Lymphedema and Lipedema)

► Show Figures

Figure 1

14 pages, 2809 KiB

Open AccessArticle

3D Spheroids Derived from Human Lipedema ASCs Demonstrated Similar Adipogenic Differentiation Potential and ECM Remodeling to Non-Lipedema ASCs In Vitro

by Sara Al-Ghadban, India A. Pursell, Zaidmara T. Diaz, Karen L. Herbst and Bruce A. Bunnell

Int. J. Mol. Sci. 2020, 21(21), 8350; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218350 - 07 Nov 2020

Cited by 15 | Viewed by 3950

Abstract

The growth and differentiation of adipose tissue-derived stem cells (ASCs) is stimulated and regulated by the adipose tissue (AT) microenvironment. In lipedema, both inflammation and hypoxia influence the expansion and differentiation of ASCs, resulting in hypertrophic adipocytes and deposition of collagen, a primary component of the extracellular matrix (ECM). The goal of this study was to characterize the adipogenic differentiation potential and assess the levels of expression of ECM-remodeling markers in 3D spheroids derived from ASCs isolated from both lipedema and healthy individuals. The data showed an increase in the expression of the adipogenic genes (ADIPOQ, LPL, PPAR-γ and Glut4), a decrease in matrix metalloproteinases (MMP2, 9 and 11), with no significant changes in the expression of ECM markers (collagen and fibronectin), or integrin A5 in 3D differentiated lipedema spheroids as compared to healthy spheroids. In addition, no statistically significant changes in the levels of expression of inflammatory genes were detected in any of the samples. However, immunofluorescence staining showed a decrease in fibronectin and increase in laminin and Collagen VI expression in the 3D differentiated spheroids in both groups. The use of 3D ASC spheroids provide a functional model to study the cellular and molecular characteristics of lipedema AT. Full article

(This article belongs to the Special Issue Current Mechanistic Understandings of Lymphedema and Lipedema)

► Show Figures

Figure 1

Review

Jump to: Research

14 pages, 662 KiB

Open AccessReview

Current Mechanistic Understandings of Lymphedema and Lipedema: Tales of Fluid, Fat, and Fibrosis

by Bailey H. Duhon, Thien T. Phan, Shannon L. Taylor, Rachelle L. Crescenzi and Joseph M. Rutkowski

Int. J. Mol. Sci. 2022, 23(12), 6621; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126621 - 14 Jun 2022

Cited by 18 | Viewed by 7398

Abstract

Lymphedema and lipedema are complex diseases. While the external presentation of swollen legs in lower-extremity lymphedema and lipedema appear similar, current mechanistic understandings of these diseases indicate unique aspects of their underlying pathophysiology. They share certain clinical features, such as fluid (edema), fat (adipose expansion), and fibrosis (extracellular matrix remodeling). Yet, these diverge on their time course and known molecular regulators of pathophysiology and genetics. This divergence likely indicates a unique route leading to interstitial fluid accumulation and subsequent inflammation in lymphedema versus lipedema. Identifying disease mechanisms that are causal and which are merely indicative of the condition is far more explored in lymphedema than in lipedema. In primary lymphedema, discoveries of genetic mutations link molecular markers to mechanisms of lymphatic disease. Much work remains in this area towards better risk assessment of secondary lymphedema and the hopeful discovery of validated genetic diagnostics for lipedema. The purpose of this review is to expose the distinct and shared (i) clinical criteria and symptomatology, (ii) molecular regulators and pathophysiology, and (iii) genetic markers of lymphedema and lipedema to help inform future research in this field. Full article

(This article belongs to the Special Issue Current Mechanistic Understandings of Lymphedema and Lipedema)

► Show Figures

Figure 1

13 pages, 547 KiB

Open AccessReview

Lipedema and the Potential Role of Estrogen in Excessive Adipose Tissue Accumulation

by Kaleigh Katzer, Jessica L. Hill, Kara B. McIver and Michelle T. Foster

Int. J. Mol. Sci. 2021, 22(21), 11720; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111720 - 29 Oct 2021

Cited by 27 | Viewed by 6324

Abstract

Lipedema is a painful fat disorder that affects ~11% of the female population. It is characterized by bilateral, disproportionate accumulation of subcutaneous adipose tissue predominantly in the lower body. The onset of lipedema pathophysiology is thought to occur during periods of hormonal fluctuation, such as puberty, pregnancy, or menopause. Although the identification and characterization of lipedema have improved, the underlying disease etiology remains to be elucidated. Estrogen, a key regulator of adipocyte lipid and glucose metabolism, and female-associated body fat distribution are postulated to play a contributory role in the pathophysiology of lipedema. Dysregulation of adipose tissue accumulation via estrogen signaling likely occurs by two mechanisms: (1). altered adipocyte estrogen receptor distribution (ERα/ERß ratio) and subsequent metabolic signaling and/or (2). increased release of adipocyte-produced steroidogenic enzymes leading to increased paracrine estrogen release. These alterations could result in increased activation of peroxisome proliferator-activated receptor γ (PPARγ), free fatty acid entry into adipocytes, glucose uptake, and angiogenesis while decreasing lipolysis, mitochondriogenesis, and mitochondrial function. Together, these metabolic alterations would lead to increased adipogenesis and adipocyte lipid deposition, resulting in increased adipose depot mass. This review summarizes research characterizing estrogen-mediated adipose tissue metabolism and its possible relation to excessive adipose tissue accumulation associated with lipedema. Full article

(This article belongs to the Special Issue Current Mechanistic Understandings of Lymphedema and Lipedema)

► Show Figures

Figure 1

18 pages, 2581 KiB

Open AccessReview

Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

by László Bálint and Zoltán Jakus

Int. J. Mol. Sci. 2021, 22(8), 3955; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083955 - 12 Apr 2021

Cited by 13 | Viewed by 3863

Abstract

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions. Full article

(This article belongs to the Special Issue Current Mechanistic Understandings of Lymphedema and Lipedema)

► Show Figures