Periodic Reporting for period 3 - LymphMap (Navigating lymphatic formation and function in health and disease) Période du rapport: 2022-02-01 au 2023-07-31 Résumé du contexte et des objectifs généraux du projet For many years, lymphatic vessels have been viewed as inert fluid conduits whose open structure allows for passive flow of antigens, proteins and cells from peripheral tissues to lymphoid organs. Yet, recent discoveries highlighting novel functions and heterogeneous origins of the lymphatic endothelium, call for the reevaluation of the passive lymphatic-vessel paradigm. During the past decade, we have used the zebrafish to detail the cellular and molecular events underlying the development of the lymphatic system. Our discoveries have greatly contributed to our understanding of the origins, specification and mechanisms of lymphatic endothelial cells formation in the developing embryo. In the present project, we aim to transform the adult zebrafish into an equally convenient model for the study of organotypic lymphatic specialization. To this end, we will first generate a comprehensive map of the lymphatic vasculature of the whole organism, from embryonic development to adulthood, and will characterize the molecular signature of different lymphatic endothelial cells at single-cell resolution. In addition, we plan to take advantage of the superb regenerative capabilities of zebrafish to investigate the role of lymphatic vessels during organ repair and regeneration. We will ask global questions on the commonalities of and differences in lymphangiogenesis among regenerating organs, including: Do all lymphatic vessels respond equally to injury? Are different origins and/or different vessel types specifically linked to specialized functions? Are there common signals for lymphatic regeneration or are the observed signals specific to each organ? Identifying the origins of newly formed lymphatic vessels and elucidating the molecular mechanisms that control their formation are key questions when considering lymphatics as a therapeutic target in regenerative medicine.As a whole, when this work is completed, we expect to have a major scientific impact on the way lymphatic vessels are perceived, no longer as a passive system, but rather as active players in tissue morphogenesis, disease and regeneration. Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent So far, on the most significant achievement of our project concerns the establishment of imaging, lineage tracing and single cell transcriptomic analyses of adult zebrafish. Since our studies are among the first to analyse organ-specific lymphatic vessels in adult zebrafish, we invested extensive efforts in the establishing the required platforms. 2. Our recent publication in Cell Reports (Jerafi-Vider et.al. 2021), which has recently been highlighted by the Israeli news (https://wis-wander.weizmann.ac.il/life-sciences/blocking-distraction-how-growing-blood-vessels-do-it-all describes the involvement of cell cycle progression in growth and differentiation of lymphatic endothelial cells. Our findings raise new questions regarding the use of cell-cycle inhibitors (for instance, during cancer treatments), as they may in fact promote blood vessel growth. Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent) Our latest work, (Das et.al BiorXiv 2021) describes for the first time the ability of lymphatic endothelial cells to generate blood vessels under physiological conditions, representing a paradigm shift in the field of lymphatic biology.
