Organ-specific mechanisms of lymphatic vascular development and specialisation

Informations projet

LYMPHORG

N° de convention de subvention: 646849

DOI

10.3030/646849

Projet clôturé

Date de signature de la CE 23 Avril 2015

Date de début 1 Mai 2015

Date de fin 30 Avril 2020

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 2 368 439,00

Contribution de l’UE

€ 2 368 439,00

Coordonné par

UPPSALA UNIVERSITET
Sweden

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

Résumé du contexte et des objectifs généraux du projet

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.

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

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.

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)

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.

Lymphatic endothelial progenitor cells in the embryonic mouse mesentery