Developmental origins of pericyte heterogeneity

PROJECT SUMMARY Heterogeneity is a hallmark of the circulatory system and is manifest in a wide range of anatomical, cellular and molecular differences that correlate with diverse blood vessel functions. A notable example of this heterogeneity is found across the distinct capillary beds in multiple different organs and tissue types. These capillary beds are the central functional unit of the circulatory system and serve as the sites for gas exchange, filtration, hormone secretion, and immune cell trafficking. Each capillary bed is uniquely tuned to its organ- specific function. For example, endothelial cells in liver capillaries are highly fenestrated and allow large macromolecules to traverse their boundaries, while brain capillaries exhibit highly selective barrier function to prevent toxic plasma components from damaging neurons. In this latter case, the function of these blood brain barrier (BBB) capillaries is governed in part by vascular mural cells known as pericytes, which share a basement membrane with endothelial cells. In the absence of pericytes, BBB function is lost, leading to leakage, deficits in neurovascular flow, and eventual neuronal apoptosis. Accordingly, recent observations indicate that pericyte loss may be a precipitating event in a number of neurodegenerative disease. Thus, pericytes play an essential role in regulating organ-specific function of capillary beds in the circulatory system. Despite their importance for vascular homeostasis, nothing is known about how pericyte identity is specified and maintained during embryonic development, in contrast to most other cardiovascular cell types. By leveraging our expertise using the zebrafish as a model system to investigate vascular development, we have applied an integrated single cell molecular approach to identify candidate transcriptional networks that may be responsible for establishing pericyte identity. Through this approach we have identified the first pericyte- specific enhancer elements, including those that display organ specificity, along with cognate transcription factors responsible for their expression. Our proposed studies will combine cutting edge genetic approaches, along with integrated cell and molecular lineage tracing, to define both general and organotypic transcriptional regulatory programs responsible for pericyte identity. Taken together, our results will shed major new insights into how this important cell type develops during embryogenesis.