Lymphatic vessels have important roles in fluid homeostasis, fat absorption, inflammation and cancer metastasis and develop in a dynamic process (called lymphangiogenesis) involving budding, migration and proliferation of lymphangioblasts. Using a genetic screen in zebrafish we identify ccbe1 (collagen and calcium-binding EGF domain-1) as indispensible for embryonic lymphangiogenesis. Ccbe1 acts at the same stage of development as Vegfc and is required for lymphangioblast budding and angiogenic sprouting from venous endothelium.
Up
to 99% of systemically administered nanoparticles are cleared
through the liver. Within the liver, most nanoparticles are thought
to be sequestered by macrophages (Kupffer cells), although significant
nanoparticle interactions with other hepatic cells have also been
observed. To achieve effective cell-specific targeting of drugs through
nanoparticle encapsulation, improved mechanistic understanding of
nanoparticle–liver interactions is required. Here, we show
the caudal vein of the embryonic zebrafish (Danio rerio) can be used as a model for assessing nanoparticle interactions
with mammalian liver sinusoidal (or scavenger) endothelial cells (SECs)
and macrophages. We observe that anionic nanoparticles are primarily
taken up by SECs and identify an essential requirement for the scavenger
receptor, stabilin-2 (stab2) in
this process. Importantly, nanoparticle–SEC interactions can
be blocked by dextran sulfate, a competitive inhibitor of stab2 and other scavenger receptors. Finally, we exploit
nanoparticle–SEC interactions to demonstrate targeted intracellular
drug delivery resulting in the selective deletion of a single blood
vessel in the zebrafish embryo. Together, we propose stab2 inhibition or targeting as a general approach for modifying nanoparticle–liver
interactions of a wide range of nanomedicines.
SUMMARYThe endothelial cells of the vertebrate lymphatic system assemble into complex networks, but local cues that guide the migration of this distinct set of cells are currently unknown. As a model for lymphatic patterning, we have studied the simple vascular network of the zebrafish trunk consisting of three types of lymphatic vessels that develop in close connection with the blood vasculature. We have generated transgenic lines that allow us to distinguish between arterial, venous and lymphatic endothelial cells (LECs) within a single zebrafish embryo. We found that LECs migrate exclusively along arteries in a manner that suggests that arterial endothelial cells serve as the LEC migratory substrate. In the absence of intersegmental arteries, LEC migration in the trunk is blocked. Our data therefore demonstrate a crucial role for arteries in LEC guidance.
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