Lymphatic support of neurogenesis and regeneration

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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 role of the meningeal lymphatic system in adult neurogenesis and regeneration and the mechanisms through which it contributes to generating new neurons during homeostasis and injury response. 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 lymphatics 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 two aims in the zebrafish as a model of adult neurogenesis and brain regeneration. Aim 1 will characterize the lymphatic response to injury using time lapse imaging and determine how disruption of the lymphatic system impacts adult neurogenesis. Using mass spectrometry, we will analyze the composition of the CSF to identify lymphangiocrine factors that support neurogenesis. In Aim 2 we will manipulate the development of the meningeal lymphatic vasculature and use transcriptomic analyses to determine the impact on immune cell populations and response. Pursuit of these hypotheses 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 forward it is critical to understand the how the lymphatic system modulates the immune and environmental aspects of neurogenesis and regeneration.