Fforde Lutter, S.C.;
Building a functional lymphatic network: a novel role for
Reelin in collecting lymphatic vessel development.
Doctoral thesis, UCL (University College London).
The mature lymphatic vasculature consists of two distinct vessel types, lymphatic capillaries and collecting lymphatic vessels, which have distinct functions in the uptake and transport of lymph respectively. However, despite the functional importance of these two vessel types, much remains unknown about the processes involved in remodelling the initially uniform lymphatic plexus into a functional hierarchy of mature vessels, and particularly the role of smooth muscle cells and the extracellular matrix in this process and in the subsequent function of collecting lymphatic vessels. Here we have identified Reelin, an extracellular matrix protein whose previous characterisation has remained largely confined to the central nervous system, as required for correct development and function of collecting lymphatic vessels. In the absence of Reelin, collecting vessels are enlarged, with a reduction in smooth muscle cell coverage and a concomitant failure to down-regulate expression of the capillary marker, LYVE-1. Unexpectedly, the canonical Reelin receptors ApoER2 and VLDLR were dispensable for normal lymphatic development, suggesting the involvement of alternative receptor(s). We have also uncovered a previously un-described mechanism for activation of Reelin signalling via interactions between smooth muscle cells and lymphatic endothelial cells, and have shown that the latter increase expression of the smooth muscle cell recruitment factor, MCP1, upon stimulation by Reelin. This work highlights the largely unexplored importance of the extracellular matrix for correct lymphatic development and function, emphasises the importance of interactions between the lymphatic endothelium and surrounding smooth muscle cells in propagating vessel development and emphasises the hitherto unrecognised importance of smooth muscle cells for lymphatic vessel morphogenesis and function.
|Title:||Building a functional lymphatic network: a novel role for Reelin in collecting lymphatic vessel development|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences|
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