Lymphatic Support of Neurogenesis and Regeneration

Weill Medical Coll Of Cornell Univ, New York NY

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Abstract

PROJECT SUMMARY The lymphatic vasculature plays a critical role in fluid homeostasis, removing cellular waste and immune responses. Recent research has highlighted its integral contribution during the regenerative response after cardiac injury. The central nervous system was until recently, believed to be immune privileged and lacking a lymphatic system. Recent studies have revealed the lymphatic system extends into the mammalian and zebrafish brain, however the role it plays in neurogenesis and the response to injury is unknown. The need to better understand how to alleviate the detrimental responses to Traumatic brain injury (TBI) and stroke and promote regeneration is imperative in order to improve outcomes. This proposal aims to uncover the different populations of meningeal lymphatic system and brain endothelial cells and study how these contribute to adult neurogenesis and regeneration. Previously, we have characterized the development of the zebrafish cardiac lymphatic system and identified the signaling pathways that regulate its specification and formation. We then demonstrated that the cardiac lymphatic vasculature expands post injury in the adult zebrafish heart. This work demonstrated that lymphatic vessels respond to injury and aid the regenerative response by trafficking immune cells. By blocking lymphangiogenesis we demonstrated that the lymphatic vasculature was required to promote regeneration and prevent scarring of heart tissue. The discovery of the meningeal lymphatics led us to hypothesize that meningeal and brain lymphatics are made up of different and changing sub-populations that uniquely support adult neurogenesis and regenerative repair after injury by providing neurotropic factors, controlling cerebral spinal fluid (CSF) composition and the immune response. To test this hypothesis, we will pursue transcriptional profiling in the zebrafish as a model of adult neurogenesis and brain regeneration. We will characterize the different populations of lymphatic endothelial cells and their response to injury using single-cell RNA sequencing analysis of meningeal lymphatic endothelial cells and brain lymphatic endothelial cells from uninjured and regenerating brains. We will generate tools to allow individual disruption of the lymphatic system components and test the impact of these on adult neurogenesis. Pursuit of this will open new avenues for investigation of lymphatic support of neurogenesis in mammalian systems in health and after injury. In order to further our comprehension of adult neurogenesis, the regenerative response of the nervous system and potential therapies for which it is critical to understand the how the lymphatic system modulates the immune and environmental aspects of neurogenesis and regeneration.