Aberrant Lymphatic Endothelial Progenitors in Lymphatic Malformation Development

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.

Basic fibroblast growth factor promotes VEGF-C-dependent lymphangiogenesis via inhibition of miR-381 in human chondrosarcoma cells

“…However, it remains unclear as to whether LECs are involved with the regulation and mechanistic functions of bFGF in chondrosarcoma. Growing evidence indicates that LECs are associated with abnormal lymphangiogenesis via the induction and modulation of VEGF-C [39, 40]. In the present study, we found that CM from bFGF-treated chondrosarcoma cells increased LEC migration and tube formation, implying that bFGF enhances lymphangiogenesis in chondrosarcoma cells.…”

NOTCH3 regulates stem-to–mural cell differentiation in infantile hemangioma

“…Although PDGFRβ and NG2 are considered mural cell markers in the vasculature (21,22), both are expressed in progenitor cells. NG2 expression has been reported in bone marrow mesenchymal stem cells (29,30), neuronal progenitor cells (31,32), and lymphatic malformation progenitor cells (33). Similarly, PDGFRβ is expressed in circulating endothelial progenitors, as well as hemangioblasts (34,35), suggesting that HemECs have failed to terminally differentiate from endothelial progenitor cells.…”

Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

“…Other models involving gene deletions or implantation of cells from human lymphatic malformations have been used to mimic human lymphatic disorders (37)(38)(39)(40). These models have proven useful in characterizing these conditions but are yet to be used to study the regression of abnormal lymphatics.…”