Regulation of lymphatic endothelial cell specification - Project Summary
The lymphatic circulation is a unique network of vessels lined by specialized lymphatic endothelial cells
(LECs), which help regulate tissue fluid homeostasis, immune cell transport, and lipid absorption. Disruption in
lymphatic vascular development leads to primary congenital lymphedema affecting 1 in 33,000 live born infants.
There are no effective cures for lymphedema, and current therapies only help mitigate symptoms of the disease.
It’s imperative to acquire a better understanding of the mechanisms that regulate lymphatic development in order
to identify novel therapeutic targets for the treatment of lymphedema, fat malabsorption and immune
surveillance. The lymphatic circulation develops in the embryo, shortly after the formation of the blood
vasculature, in a series of steps including specification, migration and maturation to form the adult lymphatic
circulation. In early embryonic development, a subset of venous endothelial cells in the cardinal vein are specified
to become LECs. Newly specified LECs migrate out of the cardinal vein forming the primitive lymphatic capillary
plexus, which is remodeled into the mature lymphatic circulation later in development. Although the progression
of lymphatic vascular development has been well described, there is still a lot unknown about the mechanisms
regulating LEC specification. Endothelial progenitor cells respond to a myriad of signaling cues to specify into
either blood, hemogenic or lymphatic endothelial fates. Recently, cell cycle state has been identified as an
important regulatory factor enabling the specification of different endothelial subtypes. Previous work from our
lab has identified cell cycle arrest in early G1 to enable venous and hemogenic endothelial specification, whereas
late G1 arrest promotes arterial fate determination. Thus, different endothelial cell cycle states dynamically
regulate endothelial cell phenotype by creating “windows of opportunity” for different fate commitments. Although
there is a growing appreciation for the role of cell cycle control in blood and hemogenic endothelial cell
specification, its contribution to LEC fate commitment during early embryogenesis remains unexplored. Our
preliminary data show that disruption of cell cycle control impairs normal LEC specification and lymphatic
vascular maturation, supporting a key role for cell cycle regulation during lymphatic development. This proposal
will test the hypothesis that G1 cell cycle arrest enables LEC specification from venous endothelial cells during
early embryogenesis. Using Fucci cell cycle reporter mice in which distinct cell cycle states can be discerned,
and novel LEC-specific knockout mouse models, we will investigate the underlying mechanisms regulating
endothelial cell cycle control and LEC specification during development. Results from these studies will help to
understand the key mechanisms at play during lymphatic vascular development and may elucidate novel
therapeutic targets for the treatment of primary lymphedemas.
