Abstract
Genetic or acquired defects of the lymphatic vasculature often result in disfiguring, disabling, and, occasionally, life-threatening clinical consequences. Advanced forms of lymphedema are readily diagnosed clinically, but more subtle presentations often require invasive imaging or other technologies for a conclusive diagnosis. On the other hand, lipedema, a chronic lymphatic microvascular disease with pathological accumulation of subcutaneous adipose tissue, is often misdiagnosed as obesity or lymphedema; currently there are no biomarkers or imaging criteria available for a conclusive diagnosis. Recent evidence suggests that otherwise-asymptomatic defective lymphatic vasculature likely contributes to an array of other pathologies, including obesity, inflammatory bowel disease, and neurological disorders. Accordingly, identification of biomarkers of lymphatic malfunction will provide a valuable resource for the diagnosis and clinical differentiation of lymphedema, lipedema, obesity, and other potential lymphatic pathologies. In this paper, we profiled and compared blood plasma exosomes isolated from mouse models and from human subjects with and without symptomatic lymphatic pathologies. We identified platelet factor 4 (PF4/CXCL4) as a biomarker that could be used to diagnose lymphatic vasculature dysfunction. Furthermore, we determined that PF4 levels in circulating blood plasma exosomes were also elevated in patients with lipedema, supporting current claims arguing that at least some of the underlying attributes of this disease are also the consequence of lymphatic defects.
Highlights
The lymphatic vasculature is a network of thin-walled initial lymphatic capillaries and larger collecting vessels covered by a continuous layer of endothelial cells providing a unidirectional conduit for filtered tissue interstitial fluids, metabolites, macromolecules, and cells toward the central venous circulation
We report on the identification of platelet factor 4 (PF4) as a plasma-circulating exosomal signature protein that could be used as a potentially novel biomarker in the clinical setting to diagnose lymphatic vasculature dysfunction and to distinguish these disorders from obesity not promoted by lymphatic disorders
Morphological and functional alterations in the lymphatic vasculature that are associated with edema at midgestation and with obesity in adult animals [18]
Summary
The lymphatic vasculature is a network of thin-walled initial lymphatic capillaries and larger collecting vessels covered by a continuous layer of endothelial cells providing a unidirectional conduit for filtered tissue interstitial fluids, metabolites, macromolecules, and cells toward the central venous circulation. One of the main disorders that ensue from malfunction of the lymphatic vasculature is lymphedema, a disfiguring, disabling, and occasionally, life-threatening clinical condition characterized by the localized interstitial accumulation of protein-rich fluid, thereby promoting tissue edema for which, at present, treatment options are few and have limited efficacy [2]. This disease affects millions worldwide and most commonly entails swelling of the extremities, tissue fibrosis, susceptibility to infections, and accumulation of subcutaneous fat [2, 3]. Overt lymphedema can be diagnosed based on the clinical context and the physical examination; more precise staging and characterization require imaging protocols that are often invasive
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