Access

Article

Nature Methods 5, 431–437 (1 May 2008) | doi:10.1038/nmeth.1205

Modeling lymphangiogenesis in a three-dimensional culture system

Fran|[ccedil]|oise Bruy|[egrave]|re , Laurence Melen-Lamalle , Silvia Blacher , Guy Roland , Marc Thiry , Lieve Moons , Francis Frankenne , Peter Carmeliet , Kari Alitalo , Claude Libert , Jonathan P Sleeman , Jean-Michel Foidart & Agn|[egrave]|s No|[euml]|l

A lack of appropriate in vitro models of three-dimensional lymph vessel growth hampers the study of lymphangiogenesis. We developed a lymphatic ring assay—a potent, reproducible and quantifiable three-dimensional culture system for lymphatic endothelial cells that reproduces spreading of endothelial cells from a pre-existing vessel, cell proliferation, migration and differentiation into capillaries. In the assay, mouse thoracic duct fragments are embedded in a collagen gel, leading to the formation of lumen-containing lymphatic capillaries, which we assessed by electron microscopy and immunostaining. We developed a computerized method to quantify the lymphatic network. By applying this model to gene-deficient mice, we found evidence for involvement of the matrix metalloproteinase, MMP-2, in lymphangiogenesis. The lymphatic ring assay bridges the gap between two-dimensional in vitro models and in vivo models of lymphangiogenesis, can be used to exploit the potential of existing transgenic mouse models, and rapidly identify regulators of lymphangiogenesis.