Periodic Reporting for period 4 - LymphMap (Navigating lymphatic formation and function in health and disease)
Berichtszeitraum: 2023-08-01 bis 2024-07-31
The LymphMap project addressed the fundamental problem of understanding how lymphatic vessels form, function, and contribute to health and disease. Lymphatic vessels are crucial for maintaining fluid balance, lipid absorption, and immune surveillance. However, despite their importance, the molecular and cellular mechanisms underlying their formation and function, particularly in adults and during disease conditions, remain poorly understood. This lack of knowledge limits the development of therapies for lymphatic-related diseases, such as lymphedema, chronic inflammatory diseases, and cancer metastasis.
Specifically, the project investigated the origins and specialization of lymphatic endothelial cells (LECs) across various organs and disease states. It sought to map the processes that govern lymphatic diversity, as well as the role lymphatic vessels play in tissue regeneration and pathological conditions.
The main objectives of the LymphMap project were to:
1. Map Lymphatic Diversity: Provide a comprehensive understanding of the cellular origins and molecular signatures of lymphatic endothelial cells (LECs) at a single-cell resolution.
2. Understand Organ-Specific Lymphatic Formation: Investigate how lymphatics are formed and specialized in various zebrafish organs, such as the heart and fins, to better understand their roles in health and disease. The project aims to reveal the molecular mechanisms driving organotypic lymphatic formation.
3. Characterize Lymphatic Function in Regeneration and Disease: Explore how lymphatic vessels contribute to organ regeneration, focusing mainly on the regenerating zebrafish heart.
4. Develop Novel Therapies: By identifying molecular pathways involved in lymphatic function and dysfunction, the project aimed to propose new therapeutic strategies.
This research is important to society for several reasons. Lymphatic vessel malfunction is associated with severe conditions like lymphedema, which causes swelling and impacts quality of life, and it contributes to chronic inflammatory diseases and cancer metastasis. By improving the understanding of lymphatic biology, better treatments can be developed for these conditions. Additionally, because lymphatic vessels play a crucial role in tissue regeneration and immune responses, insights into lymphatic function could lead to novel regenerative therapies, particularly for conditions such as myocardial infarction and tissue damage. Moreover, cancer frequently spreads through the lymphatic system, making it a target for therapies aimed at preventing metastasis. Understanding how lymphatics form and operate will provide new opportunities for combatting cancer progression.
Specifically, the project investigated the origins and specialization of lymphatic endothelial cells (LECs) across various organs and disease states. It sought to map the processes that govern lymphatic diversity, as well as the role lymphatic vessels play in tissue regeneration and pathological conditions.
The main objectives of the LymphMap project were to:
1. Map Lymphatic Diversity: Provide a comprehensive understanding of the cellular origins and molecular signatures of lymphatic endothelial cells (LECs) at a single-cell resolution.
2. Understand Organ-Specific Lymphatic Formation: Investigate how lymphatics are formed and specialized in various zebrafish organs, such as the heart and fins, to better understand their roles in health and disease. The project aims to reveal the molecular mechanisms driving organotypic lymphatic formation.
3. Characterize Lymphatic Function in Regeneration and Disease: Explore how lymphatic vessels contribute to organ regeneration, focusing mainly on the regenerating zebrafish heart.
4. Develop Novel Therapies: By identifying molecular pathways involved in lymphatic function and dysfunction, the project aimed to propose new therapeutic strategies.
This research is important to society for several reasons. Lymphatic vessel malfunction is associated with severe conditions like lymphedema, which causes swelling and impacts quality of life, and it contributes to chronic inflammatory diseases and cancer metastasis. By improving the understanding of lymphatic biology, better treatments can be developed for these conditions. Additionally, because lymphatic vessels play a crucial role in tissue regeneration and immune responses, insights into lymphatic function could lead to novel regenerative therapies, particularly for conditions such as myocardial infarction and tissue damage. Moreover, cancer frequently spreads through the lymphatic system, making it a target for therapies aimed at preventing metastasis. Understanding how lymphatics form and operate will provide new opportunities for combatting cancer progression.
Conclusions and Main Achievements of LymphMap:
LymphMap has provided significant insights into lymphatic vessel biology.
1. The project has uncovered distinct lymphatic progenitor populations and revealed, for the first time, that lymphatic vessels can transdifferentiate into specialized blood vessels in adult organisms. These results, published in Das et.al Nature, 2022 (https://pubmed.ncbi.nlm.nih.gov/35614218/(öffnet in neuem Fenster)) represent a paradigm shift in the field of lymphatic biology
2. We have also identified new molecular pathways, such as cell-cycle control, as critical regulators of lymphatic sprouting and differentiation, offering promising new directions for therapeutic intervention (https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00620-3(öffnet in neuem Fenster)).
3. The project has successfully mapped lymphatic diversity, demonstrated the complex roles of lymphatic vessels in cardiac function and regeneration, and laid the groundwork for future medical developments aimed at improving cardiac repair following injury by targeting the lymphatic system (https://elifesciences.org/articles/44153(öffnet in neuem Fenster); https://pubmed.ncbi.nlm.nih.gov/31818858/(öffnet in neuem Fenster)).
4. We have established a novel zebrafish model of Kaposiform Lymphangiomatosis- a rare, aggressive, and incurable disease caused by a somatic activating NRAS mutation (p.Q61R) in lymphatic endothelial cells (LECs). We found that mutant embryos recapitulated clinical features of KLA and leveraged this model in combination with an AI-based high-throughput drug screening platform to search for small compounds selectively reverting the mutant phenotypes (https://www.biorxiv.org/content/10.1101/2024.03.21.586124v1.full(öffnet in neuem Fenster))
LymphMap has provided significant insights into lymphatic vessel biology.
1. The project has uncovered distinct lymphatic progenitor populations and revealed, for the first time, that lymphatic vessels can transdifferentiate into specialized blood vessels in adult organisms. These results, published in Das et.al Nature, 2022 (https://pubmed.ncbi.nlm.nih.gov/35614218/(öffnet in neuem Fenster)) represent a paradigm shift in the field of lymphatic biology
2. We have also identified new molecular pathways, such as cell-cycle control, as critical regulators of lymphatic sprouting and differentiation, offering promising new directions for therapeutic intervention (https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00620-3(öffnet in neuem Fenster)).
3. The project has successfully mapped lymphatic diversity, demonstrated the complex roles of lymphatic vessels in cardiac function and regeneration, and laid the groundwork for future medical developments aimed at improving cardiac repair following injury by targeting the lymphatic system (https://elifesciences.org/articles/44153(öffnet in neuem Fenster); https://pubmed.ncbi.nlm.nih.gov/31818858/(öffnet in neuem Fenster)).
4. We have established a novel zebrafish model of Kaposiform Lymphangiomatosis- a rare, aggressive, and incurable disease caused by a somatic activating NRAS mutation (p.Q61R) in lymphatic endothelial cells (LECs). We found that mutant embryos recapitulated clinical features of KLA and leveraged this model in combination with an AI-based high-throughput drug screening platform to search for small compounds selectively reverting the mutant phenotypes (https://www.biorxiv.org/content/10.1101/2024.03.21.586124v1.full(öffnet in neuem Fenster))
Our latest work (Das et.al Nature, 2022) 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.