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Open Access Highly Accessed Research article

Digging deeper into lymphatic vessel formation in vitro and in vivo

Benoit Detry1, Françoise Bruyère1, Charlotte Erpicum1, Jenny Paupert1, Françoise Lamaye3, Catherine Maillard1, Bénédicte Lenoir1, Jean-Michel Foidart12, Marc Thiry3 and Agnès Noël1*

Author Affiliations

1 Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique appliqué-Recherche (GIGA-Cancer), University of Liège, B-4000 Liège, Belgium

2 Department of Gynecology, CHU, B-4000 Liège, Belgium

3 Laboratory of Cell and Tissue Biology, Groupe Interdisciplinaire de Génoprotéomique appliqué-Recherche (GIGA-Neurosciences), University of Liège, B-4000, Liège, Belgium

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BMC Cell Biology 2011, 12:29  doi:10.1186/1471-2121-12-29

Published: 24 June 2011

Abstract

Background

Abnormal lymphatic vessel formation (lymphangiogenesis) is associated with different pathologies such as cancer, lymphedema, psoriasis and graft rejection. Lymphatic vasculature displays distinctive features than blood vasculature, and mechanisms underlying the formation of new lymphatic vessels during physiological and pathological processes are still poorly documented. Most studies on lymphatic vessel formation are focused on organism development rather than lymphangiogenic events occurring in adults. We have here studied lymphatic vessel formation in two in vivo models of pathological lymphangiogenesis (corneal assay and lymphangioma). These data have been confronted to those generated in the recently set up in vitro model of lymphatic ring assay. Ultrastructural analyses through Transmission Electron Microscopy (TEM) were performed to investigate tube morphogenesis, an important differentiating process observed during endothelial cell organization into capillary structures.

Results

In both in vivo models (lymphangiogenic corneal assay and lymphangioma), migrating lymphatic endothelial cells extended long processes exploring the neighboring environment and organized into cord-like structures. Signs of intense extracellular matrix remodeling were observed extracellularly and inside cytoplasmic vacuoles. The formation of intercellular spaces between endothelial cells led to tube formation. Proliferating lymphatic endothelial cells were detected both at the tips of sprouting capillaries and inside extending sprouts. The different steps of lymphangiogenesis observed in vivo are fully recapitulated in vitro, in the lymphatic ring assay and include: (1) endothelial cell alignment in cord like structure, (2) intracellular vacuole formation and (3) matrix degradation.

Conclusions

In this study, we are providing evidence for lymphatic vessel formation through tunneling relying on extensive matrix remodeling, migration and alignment of sprouting endothelial cells into tubular structures. In addition, our data emphasize the suitability of the lymphatic ring assay to unravel mechanisms underlying lymphangiogenesis.