Lymphatic Development and Maintenance
Notch signaling is an evolutionarily conserved signaling pathway that modulates cellular responses to extracellular cues and is necessary for blood vascular development. Using conditional drivers that activate or inactivate Notch signaling in the lymphatic endothelium at different time-points during embryogenesis, we discovered that Notch is essential in the lymphatic vasculature. It regulates venous to lymphatic endothelial cell specification and lymphatic collective duct valve morphogenesis. Moreover, Notch activation during lymphatic endothelial cell specification results in massive embryonic edema reminiscent to human fetal hydrops. These studies suggest that Notch has multiple roles in the lymphatics. Current studies are focused on the role of Notch in regulating the extracellular matrix via induction of matrix metalloproteinases in embryonic, intestinal, and mesenteric lymphatics. The overall goals are to use conditional and cell-type specific mouse models to understand the molecular mechanisms by which Notch functions in lymphatic vascular under both physiological and pathological lymphangiogenesis and lymphatic maintenance.
Fetal and Pediatric Lymphatic Anomalies
In humans, a majority of lymphatic anomalies develop in the fetus or within the first 5 years of life. Our lab focuses on two forms of lymphatic anomalies: congenital lymphatic malformations (LM) and idiopathic congenital chylothorax. LMs occur in 1:3500 to 1:8000 births and are associated with debilitating morbidities and death in affected individuals. Morbidities include hemorrhage, bone destruction and overgrowth, respiratory failure, recurrent infections and sepsis. Congenital chylothorax is the accumulation of chyle or lymph in the thoracic cavity and patients suffer from neonatal respiratory mobidity, malnutrition and repeat infections. Congenital chylothorax patients have a 16% mortality rate by 10 years of age. Both these lymphatic anomalies have high recurrence rates (25-50%) and often require hospitalizations and intensive treatments. We recently identified and isolated novel lymphatic malformation progenitor cells (LMPCs) from specimens from LMs and congenital chylothoraxes. Using LMPCs, we developed a novel pre-clinical LM mouse model that recapitulates many hallmarks of the human LM pathology. Combining a drug screen using LMPCs and the LM mouse model, we identified propranolol, a beta-adrenergic inhibitor, as a potential therapy. We are currently in the process of developing a trial to test propranolol in fetal congenital chylothorax and pediatric and adult lymphedema. Current studies in the lab focus on understanding the molecular mechanisms by which beta-adrenergic and Notch signaling function in lymphatic anomalies. The overall goals are to develop a better biological understanding of lymphatic anomalies that will allow us to devise improved and more effective therapies for affected fetuses and children.
Lymphatics and Differential Fat Deposition
The lymphatics function to uptake fat and fat-soluble nutrients from the intestines, while chyle promotes differentiation of fat cells. Our studies focus on understanding the role of lymphatics in the fat disorder, lipedema. Lipedema is a poorly understood disorder that involves wide spread and uniform distribution of subcutaneous fat mostly restricted to the low extremities. Lipedema has a female preponderance affecting 5-10% of post-pubertal females (est. 17 mil US women, 370 mil women worldwide). It is progressive leading to debilitating morbidities (pain, tissue fibrosis, edema) and psychological problems. The pathobiology of lipedema is unknown and current interventions are palliative. As lipedema is often under-diagnosed or miss-diagnosed, these patients are in urgent need of new diagnostics. Our studies have shown that Notch4 mutant mice recapitulate many of the hallmarks of lipedema. We are currently developing mouse models to conditionally delete Notch4 in the lymphatic endothelial cells to determine its role in the abnormal and specific accumulation of subcutaneous fat. These studies are complimented by studies using isolated lymphatic endothelial cells from lipedema patients. Patient-derived cells will be used to develop a preclinical model, in a high throughput drug screen, and in a high throughput genetic and epigenetic screen to identify the causes of lipedema, as well as potential therapeutic targets. We also aim to develop new imaging methods to improve lipedema diagnosis. The overall goals are to understand the roles of lymphatics in the development and progression of lipedema, and to develop new diagnostic tools, and a pre-clinical mouse model to test potential new therapies.
Lymphatic Vascular Defects and Aneuploidy
Chromosomal aneuploidies are often associated with increased nuchal edema or fetal hydrops. It is hypothesized that the edema arises from defects in lymphatic vascular development. However, the lymphatic phenotypes and molecular causes are poorly understood. Our studies focus on lymphatic vascular development in Trisomy 21 (Down’s Syndrome) and Monosomy X (Turner Syndrome) fetuses. We find that mid-gestation Turner’s tissues display both blood capillary and lymphatic vascular defects characterized by abnormal vascular smooth muscle cell coverage of lymphatic capillaries. This improper vascular smooth muscle coverage in Turner’s fetuses may contribute to the edema. We are currently extending our studies into the possible role of Notch in lymphatic vascular defect associated with aneuploidy. The overall goal is to improve our understanding into the molecular cause of lymphatic vascular defects associated with fetal edema.