title: 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.
authors.affiliation: Department of Surgery, College of Physicians & Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: June K
authors.initials: JK
authors.lastname: Wu
authors.affiliation: Department of Ob/Gyn, College of Physicians & Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kitajewski
authors.affiliation: Department of Ob/Gyn, College of Physicians & Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Maia
authors.initials: M
authors.lastname: Reiley
authors.affiliation: Department of Surgery, College of Physicians & Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Connie H
authors.initials: CH
authors.lastname: Keung
authors.affiliation: Department of Surgery, College of Physicians & Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Monteagudo
authors.affiliation: Department of Surgery, College of Physicians & Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Andrews
authors.affiliation: Department of Surgery, College of Physicians & Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Liou
authors.affiliation: Department of Surgery, College of Physicians & Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Arul
authors.initials: A
authors.lastname: Thirumoorthi
authors.affiliation: Department of Surgery, College of Physicians & Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Alvin
authors.initials: A
authors.lastname: Wong
authors.affiliation: Department of Surgery, the University of Chicago Medicine, Chicago, Illinois, United States of America.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Kandel
authors.affiliation: Department of Surgery, College of Physicians & Surgeons, Columbia University, New York, New York, United States of America; Department of Ob/Gyn, College of Physicians & Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Carrie J
authors.initials: CJ
authors.lastname: Shawber
mesh_terms: D000293:Adolescent; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D066026:Endothelial Progenitor Cells / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D042601:Lymphatic Vessels / Q000002:abnormalities* / Q000166:cytology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein; D000098853:Podoplanin
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D025521:Tumor Suppressor Proteins; D040321:Vascular Endothelial Growth Factor Receptor-3; D033921:Vesicular Transport Proteins; D000098551:Prospero-Related Homeobox 1 Protein; C119248:LYVE1 protein, human; C486780:NANOG protein, human; C117468:PDPN protein, human; D000098853:Podoplanin; C494173:POU5F1 protein, human; C581309:FLT4 protein, human