Periodic Reporting for period 4 - LYMPHORG (Organ-specific mechanisms of lymphatic vascular development and specialisation)
Période du rapport: 2019-11-01 au 2020-04-30
Pathological lymphatic diseases mostly affect vessels of specific tissues, yet organ-specific regulation of lymphatic development and function remain unexplored. This project aimed to identify genes and mechanisms regulating organ-specific lymphatic vascular development and explore the therapeutic potential of our newly identified tissue-specific lymphatic endothelial progenitor cell (LEPC). Using advanced mouse genetics, imaging and single cell transcriptomics, we identified novel mechanisms controlling lymphatic vessel formation from progenitors of non-venous and venous origins, and established tools for the functional characterization of LEPCs and the process of lymphvasculogenesis. Our results provide fundamental new insights into how lymphatic vessels are formed, but they may also create a better understanding of the reasons for common diseases characterized by (organ-specific) impairment of lymphatic function.
Building on our discovery of a previously unknown progenitor cell type that is required for lymphatic vessel development in an organ-specific manner, we aimed to identify the origin and function of lymphatic endothelial progenitor cells (LEPCs) during development, and to assess their potential for therapeutic lymphatic regeneration. Towards this aim, we have performed single cell RNA sequencing of LECs of mouse embryonic mesenteries, which will be utilized to identify the (mesenteric) LEPC specific transcriptome. In addition, we have developed and characterized novel transgenic models and methodology for the purpose of targeting and studying non-venous derived LEPCs and the lymphvasculogenic process of vessel formation in vivo and ex vivo. Analysis of genetic mouse models has further uncovered novel mechanisms controlling lymphatic vessel formation from progenitors of both non-venous and venous origins. Research results have been presented in major international vascular biology conferences, and published in peer-reviewed scientific journals.
Single cell transcriptome data generated for LECs of early embryonic mesenteries will be used for unambiguous molecular definition of LEPCs. New methodology and genetic tools have been established to allow reconstruction of early mesenteric vascular development and dynamic studies of lymphvasculogenic vessel formation ex vivo. Together these data and tools will allow studying the functional properties of non-venous derived LEC progenitors.