Shibata-Germanos, Shannon Mica;
(2020)
The Structural and Functional Conservation of a Vertebrate Meningeal Phagocyte with a Lymphatic Molecular Signature.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
The vertebrate CNS is surrounded by the meninges, a protective barrier comprised of the outer dura mater and the inner leptomeninges, which includes the arachnoid and pial layers. While the dura mater contains lymphatic vessels, no conventional lymphatics have been found within the brain parenchyma or leptomeninges. Here I report evidence of a lymphatic endothelial-derived cell population within the inner layers of the meninges of the zebrafish CNS, nearest to the parenchymal surface of the brain, with a venous origin that proliferate to form a loosely connected network of cells in close association with blood vasculature. These cells were named Brain Lymphatic Endothelial Cell (BLECs) as they exhibit critical hallmarks of lymphatic identity yet do not lumenize to form vessels in steady state conditions. BLECs appear distinct from other known cell types, combining the structural and molecular features of endothelial cells with functional characteristics of macrophages and microglial cells. BLECs are able to take up macromolecules ranging in size from 10kDa to 500kDa with uptake dependent on endocytosis via the pattern recognition mannose receptor (MR). I also identified a structurally and functionally similar cell type in the mammalian leptomeninges, newly named Leptomeningeal Lymphatic Endothelial Cells (LLEC). As in zebrafish, LLECs express multiple lymphatic markers, contain very large, spherical inclusions, and develop independently from the meningeal macrophage lineage. Much like zebrafish BLECs, mouse LLECs internalize macromolecules from the cerebrospinal fluid, including amyloid-β, the toxic driver of Alzheimer’s disease progression. Finally, morphologically similar cells co-expressing BLEC/LLEC markers are found in human post-mortem leptomeninges. Given that BLECs and LLECs share molecular, morphological, and functional characteristics with both lymphatics and macrophages, they likely represent a novel, evolutionary conserved cell type with potential roles in homeostasis and immune organisation of the meninges.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The Structural and Functional Conservation of a Vertebrate Meningeal Phagocyte with a Lymphatic Molecular Signature |
| Event: | UCL |
| Language: | English |
| Keywords: | Lymphatics, Meninges, Neuroimmunology, CNS Lymphatics |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10089305 |
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