Abstract
Lymphatic malformations (LMs) are vascular anomalies thought to arise from dysregulated lymphangiogenesis. These lesions impose a significant burden of disease on affected individuals. LM pathobiology is poorly understood, hindering the development of effective treatments. In the present studies, immunostaining of LM tissues revealed that endothelial cells lining aberrant lymphatic vessels and cells in the surrounding stroma expressed the stem cell marker, CD133, and the lymphatic endothelial protein, podoplanin. Isolated patient-derived CD133+ LM cells expressed stem cell genes (NANOG, Oct4), circulating endothelial cell precursor proteins (CD90, CD146, c-Kit, VEGFR-2), and lymphatic endothelial proteins (podoplanin, VEGFR-3). Consistent with a progenitor cell identity, CD133+ LM cells were multipotent and could be differentiated into fat, bone, smooth muscle, and lymphatic endothelial cells in vitro. CD133+ cells were compared to CD133− cells isolated from LM fluids. CD133− LM cells had lower expression of stem cell genes, but expressed circulating endothelial precursor proteins and high levels of lymphatic endothelial proteins, VE-cadherin, CD31, podoplanin, VEGFR-3 and Prox1. CD133− LM cells were not multipotent, consistent with a differentiated lymphatic endothelial cell phenotype. In a mouse xenograft model, CD133+ LM cells differentiated into lymphatic endothelial cells that formed irregularly dilated lymphatic channels, phenocopying human LMs. In vivo, CD133+ LM cells acquired expression of differentiated lymphatic endothelial cell proteins, podoplanin, LYVE1, Prox1, and VEGFR-3, comparable to expression found in LM patient tissues. Taken together, these data identify a novel LM progenitor cell population that differentiates to form the abnormal lymphatic structures characteristic of these lesions, recapitulating the human LM phenotype. This LM progenitor cell population may contribute to the clinically refractory behavior of LMs.
Highlights
Vascular anomalies are a heterogeneous group of lesions with arterial, venous, or lymphatic components that develop in utero or shortly after birth
We have identified and isolated lymphatic malformation progenitor cells from lymphatic malformations (LMs) patients
CD133+/podoplanin+ lymphatic malformation progenitor cell (LMPC) were observed in the abnormal lymphatic endothelium and adjacent parenchyma of LM tissues, independent of anatomic location or sub-type, suggesting that LMPCs are common to lymphatic anomalies
Summary
Vascular anomalies are a heterogeneous group of lesions with arterial, venous, or lymphatic components that develop in utero or shortly after birth. These lesions are classified into malformations and tumors, based on histological classification, endothelial cell morphology, and clinical behavior [1,2,3]. Individuals with LMs are subject to significant morbidities resulting from disruption of these essential functions, including lymphedema, lymphatic fluid pooling (chylous ascites and chylothorax), and intralesional bleeding. Superinfection of tissues in which lymphatic flow is impaired can lead to overwhelming sepsis. Despite this significant burden of disease, the pathobiology of these lesions is poorly understood
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