Single-Cell Transcriptional Heterogeneity of Lymphatic Endothelial Cells in Normal and Inflamed Murine Lymph Nodes

Abstract

The lymphatic system plays a crucial role in immunity and lymph nodes (LNs) undergo drastic remodeling during inflammation. Here, we used single-cell RNA sequencing to investigate transcriptional changes in lymphatic endothelial cells (LECs) in LNs draining naïve and inflamed skin. We found that subsets of LECs lining the different LN sinuses responded individually to skin inflammation, suggesting that they exert distinct functions under pathological conditions. Among the genes dysregulated during inflammation, we confirmed an up-regulation of CD200 in the LECs lining the subcapsular sinus floor with a possible function in immune regulation. Furthermore, by in silico analysis, we predicted numerous possible interactions of LECs with diverse immune cells in the LNs and found similarities in the transcriptional changes of LN LECs in different skin inflammation settings. In summary, we provide an in-depth analysis of the transcriptional landscape of LN LECs in the naïve state and in skin inflammation.

Altered Heterogeneity of Ageing Lung Endothelium is a Hallmark of Idiopathic Pulmonary Fibrosis

“…To our knowledge, the present study is the first description of distinct molecular signatures of LEC sub-clusters, revealing the heterogeneity of ageing human lung lymphatic endothelium. No studies analysed the transcriptional profile of lymphatic vessel endothelium at a single cell level in the mouse or human lung (from either ageing or young patients), or any other organs, except lymph nodes (54)(55)(56). Previously unrecognised heterogeneity of ageing human LEC warrants further study to decipher their role in lung tissue.…”

Single-Cell RNA Sequencing Reveals Heterogeneity and Functional Diversity of Lymphatic Endothelial Cells

“…LECs mark the outline of SCS, CS, and MS in the LN, along with other stromal cells, such as fibroblastic reticular cells and perivascular cells [ 50 ]. ScRNA-seq studies have revealed transcriptomic differences between LEC populations lining these different parts of the LN, and they have identified subpopulations that delineate the floor of SCS (floor LECs), the ceiling of the SCS (ceiling LECs), the medullary sinus (medullary LECs), and the cortical sinus (cortical LECs) [ 51 , 52 , 53 ]. Figure 2 gives an overview of the different subpopulations, their spatial location, markers, and proposed functions.…”

“…The ceiling LECs of the SCS that are adjacent to the LN capsule seem to affect transport of immune cells in a different way. In contrast to floor LECs, scRNA-seq data revealed expression of the chemokine scavenging receptor ACKR4 and Ackr3 [ 51 , 52 , 53 ]. Chemokine scavenging receptors create chemokine gradients to guide immune cell transport, and their expression is unique to ceiling LECs.…”

Editorial: Molecular Mechanisms and Signaling in Endothelial Cell Biology and Vascular Heterogeneity

“…Nevertheless, with the first successful isolation and primary culture of human ECs from umbilical veins independently by Jaffe et al (1973a) and Jaffe et al (1973b) and Gimbrone et al (1974), extensive studies on EC biology and growth of new blood vessels have started at molecular and cellular levels and by using animal models and human patient samples. Along with the discovery of tools for the culture of vascular and lymphatic ECs and other new models and technologies, the concept of the heterogeneity of ECs and blood and lymphatic vessels is getting increased recognition as an important feature of vascular biology by several researchers and scientists in various disciplines of biomedical research (Aird, 2006;Kang et al, 2010;Yuan et al, 2016;Mojiri et al, 2019;Ren et al, 2019;Takeda et al, 2019;Turgeon et al, 2020;Xiang et al, 2020;Sibler et al, 2021). It is known that ECs can interact with the blood constituents such as RBCs and can also interact with cells in a tissue that they reside in to influence functions (Cao et al, 2017;Kumar et al, 2019;Akil et al;Jiang et al, 2021).…”