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Early Lymph Vessel Development From Embryonic Stem Cells

From the Department of Genetics and Pathology (J.K., I.N., L.C.-W.) Uppsala University, Sweden; the Department of Pathology (D.K.), University of Vienna Medical School, Austria; Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research (T.P., K.A.), Helsinki University Central Hospital, Finland.

Correspondence to Johan Kreuger, The Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Dag Hammarskjöldsv. 20, SE-75185 Uppsala, Sweden. E-mail johan.kreuger{at}genpat.uu.se

Objective— The purpose of this study was to establish a model system for lymph vessel development based on directed differentiation of murine embryonic stem cells.

Methods and Results— Stem cells were aggregated to form embryoid bodies, and subsequently cultured in 3-dimensional collagen matrix for up to 18 days. Treatment with vascular endothelial growth factor (VEGF)-C and VEGF-A individually enhanced formation of lymphatic vessel structures, although combined treatment with VEGF-C and VEGF-A was most potent and gave rise to a network of LYVE-1, podoplanin, Prox1, and VEGF receptor-3 positive lymphatic vessel structures running parallel to and apparently emanating from, capillaries. In contrast, fibroblast growth factor-2, hepatocyte growth factor, or hypoxia had little or no effect on the development of the early lymphatics. Further, cells of hematopoietic origin were shown to express lymphatic markers. In summary, different subpopulations of lymphatic endothelial cells were identified on the basis of differential expression of several lymphatic and blood vessel markers, indicating vascular heterogeneity.

Conclusions— We conclude that the present model closely mimics the early steps of lymph vessel development in mouse embryos.

We have established a model system for lymph vessel development based on directed differentiation of murine embryonic stem cells. Vascular endothelial growth factors, but not other growth factors tested, or hypoxia, induced lymph vessel formation, indicating different mechanisms of lymph vessel formation during embryonic development and in the adult.

Key Words: embryoid body • lymphangiogenesis • LYVE-1 • Prox1 • VEGF-C • VEGF receptor-3

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