Transcription Factor Control of Lymphatic Quiescence and Maturation of Lymphatic Neovessels in Development and Physiology

Abstract

The lymphatic system is a vascular system comprising modified lymphatic endothelial cells, lymph nodes and other lymphoid organs. The system has diverse, but critical functions in both physiology and pathology, and forms an interface between the blood vascular and immune system. It is increasingly evident that remodelling of the lymphatic system occurs alongside remodelling of the blood microvascular system, which is now considered a hallmark of most pathological conditions as well as being critical for normal development. Much attention has focussed on how the blood endothelium undergoes phenotypic switching in development and disease, resulting in over two decades of research to probe the mechanisms underlying the resulting heterogeneity. The lymphatic system has received less attention, and consequently there are fewer descriptions of functional and molecular heterogeneity, but differential transcription factor activity is likely an important control mechanism. Here we introduce and discuss significant transcription factors of relevance to coordinating cellular responses during lymphatic remodelling as the lymphatic endothelium dynamically changes from quiescence to actively remodelling.

Keywords: inflammation; lymphangiogenesis; lymphatic; quiescence; transcription factor.

FIGURE 1

Comparison of a lymphatic collecting vessel and a lymphatic capillary. Further to lumen calibre differences, additional features of collecting vessels include pericyte coverage, a layer of smooth muscle cells and the presence of valves to prevent backflow. Capillaries have discontinuous junctions between endothelial cells, these act as sights of leukocyte entry and increase the permeability of the vessel. Additionally, capillaries are connected to the extracellular matrix by anchoring filaments, these become taut in places of swelling, opening the lumen to allow drainage of tissue fluid. Adapted from Tammela and Alitalo (2010). Made with Biorender.com.

FIGURE 2

Development, differentiation and separation of the blood and lymphatic networks. Both networks originate from progenitors in the mesodermal layer of the embryo. From the primitive vascular plexus, transcription factors activate the innate genetic programme, resulting in extensive remodelling cascades throughout embryogenesis, forming two distinct networks of vessels. In the heart, the lymphatic plexus is remodelled and guided by tissue-resident macrophages through direct interaction between the lymphatic endothelial cells and the macrophages. Adapted from De Val and Black (2009) and Adams and Alitalo (2007). Created using BioRender.com.

FIGURE 3

Transcriptional insight into establishment and regulation of the quiescent lymphatic endothelial phenotype. A dynamic and interchangeable network of transcription factors are involved in the complex signalling which differentiates and maintains expression of essential proteins within the cell. This allows the cell to respond accordingly to external stimuli and retain structural stability in areas of high stress. Made with Biorender.com.