Tissue-specific endothelial cell heterogeneity contributes to unequal inflammatory responses

Abstract

Endothelial cells (EC) coordinate vascular homeostasis and inflammation. In organ transplantation, EC are a direct alloimmune target. We posited that tissue specific heterogeneity of vascular EC may partly underlie the disparate organ-specific alloimmune risk. We examined the vascular endothelial response to inflammation across six primary endothelial beds from four major transplanted organs: the heart, lung, kidney and liver. First, we reanalyzed a public dataset of cardiac allograft rejection and found that endothelial inflammatory response genes were elevated in human cardiac allograft biopsies undergoing rejection compared with stable grafts. Next, the inducible inflammatory phenotypes of EC from heart, lung, kidney, and liver were characterized in vitro, focused on expression of adhesion molecules and chemokines, and recruitment of allogeneic peripheral blood mononuclear immune cells. Large vessel cardiac EC most highly upregulated VCAM-1, particularly compared with hepatic EC, supported greater leukocyte adhesion and had distinct chemokine profiles after stimulation with cytokines and complement. Differentially expressed gene candidates that are known regulators of cytokine signaling and inflammatory programming were verified in publicly available datasets of organ-specific endothelial transcriptomes. In summary, differential baseline expression of immune regulating genes may contribute to differential vascular inflammatory responses depending on organ.

Sex‐Specific Response to Combinations of Shear Stress and Substrate Stiffness by Endothelial Cells In Vitro

“…These may include the influence of molecular contributors such as past environments and epigenetic changes, donor demographics and medical history, donor genetic variability, the species and tissue origin of the donor cells, and the lack and inclusion of cellcell interaction by self and other cell types. [11,43,[93][94][95][96][97][98][99][100][101][102][103] They also take the form of environmental contributors such as the choice of stimulating device, the choice of substrate material and extracellular matrix protein used for attachment, the collection of mechanical and chemical factors omitted from investigation, the range of stimuli included for investigation, the supplements included in cell culture media formulations, and the influence of sex hormones. [1,45,47,[104][105][106][107][108] Addressing all of these molecular and environmental contributors is untenable for the in vitro medium, thus the best course of action is to recognize these contributors and report in sufficient detail the information that is known and unknown.…”

“…[99][100][101] Similarly, endothelial cells display tremendous heterogeneity in their behavior depending on their tissue of origin. [95][96][97][98] Such effects have been observed to interact with biological sex, as well. [46] Consequently, it is necessary to expand upon our findings by evaluating not only HUVECs, but other endothelial cell types derived from other vessels such as the aorta, carotid artery, or microvasculature.…”

Endothelial Heterogeneity in Development and Wound Healing

“…This includes the regulation of pro-and anti-coagulant production, expression of E-and P-selectins to induce leukocyte rolling and expression of vascular cell adhesion molecules such as VCAM and ICAM to induce leukocyte adhesion and recruitment (reviewed in [6]). Intriguingly, while inflammation seems to activate a broadly similar inflammatory response, there is a persistent tissue-specific heterogeneity of endothelial cells in response to inflammation [69]. Examples include particular upregulation of P-selectin-a key mediator of platelet activation and aggregation-in heart and brain, which are tissues that are susceptible to thrombotic events, whereas lung endothelial cells have a marked upregulation of specific chemokines such as Cxcl1 and Cxcl9 [60].…”

Mitomycin-Treated Endothelial and Smooth Muscle Cells Suitable for Safe Tissue Engineering Approaches

“…Transcriptomic analysis revealed specific pathways, transporters, and cell-surface markers expressed in the endothelium of each organ ( Jambusaria et al, 2020 ). Recently identified 37 differentially expressed immune-related genes across ECs from different anatomic origins ( Gunawardana et al, 2021 ). Endothelial heterogeneity contributes to the response of an organism to organ and tissue transplantation.…”