Wednesday, August 10, 2022
8/10/2022
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.
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