Fenestrated Endothelial Cells across Organs: Insights into Kidney Function and Disease

Abstract

In the human body, the vascular system plays an indispensable role in maintaining homeostasis by supplying oxygen and nutrients to cells and organs and facilitating the removal of metabolic waste and toxins. Blood vessels-the key constituents of the vascular system-are composed of a layer of endothelial cells on their luminal surface. In most organs, tightly packed endothelial cells serve as a barrier separating blood and lymph from surrounding tissues. Intriguingly, endothelial cells in some tissues and organs (e.g., choroid plexus, liver sinusoids, small intestines, and kidney glomerulus) form transcellular pores called fenestrations that facilitate molecular and ionic transport across the vasculature and mediate immune responses through leukocyte transmigration. However, the development and unique functions of endothelial cell fenestrations across organs are yet to be fully uncovered. This review article provides an overview of fenestrated endothelial cells in multiple organs. We describe their development and organ-specific roles, with expanded discussions on their contributions to glomerular health and disease. We extend these discussions to highlight the dynamic changes in endothelial cell fenestrations in diabetic nephropathy, focal segmental glomerulosclerosis, Alport syndrome, and preeclampsia, and how these unique cellular features could be targeted for therapeutic development. Finally, we discuss emerging technologies for in vitro modeling of biological systems, and their relevance for advancing the current understanding of endothelial cell fenestrations in health and disease.

Keywords: disease models; endothelial cells; fenestrations; glomerulus; kidney disease; microphysiological systems; vasculature.

Figure 1

Schematic illustration of endothelial fenestration development and their distribution in various human organs. (A) Types of endothelial cell fenestrations, including diaphragmed fenestrations with PLVAP-positive diaphragms (top), non-diaphragmed fenestrations (middle), and non-diaphragmed “discontinuations” with intercellular gaps (bottom). Created with BioRender (https://app.biorender.com/, accessed on 22 July 2024). (B) Developmental pathways implicated in endothelial fenestrations and downstream of VEGF signaling. NO: Nitric oxide. Created with BioRender (https://app.biorender.com/, accessed on 22 July 2024). (C) Hypothesis of structural changes in endothelial cells during fenestration development. Created with BioRender. (D) Schematic of a human body highlighting various organs that contain fenestrated endothelial cells. Endothelial cells are labeled in pink. Created with BioRender (https://app.biorender.com/, accessed on 22 July 2024).

Figure 2

Illustration of glomerular endothelial cells in kidney glomerulus under healthy condition at the tissue level, with size-selective filtration function (top left) and at the molecular level with non-diaphragmed endothelial fenestrations (top right), compared to diseased condition at the tissue level with the loss of size-selective filtration function (bottom left) and at the molecular level with the presence of fenestration diaphragms (PLVAP-positive) along with increased VEGF signaling (bottom right). Glomerular endothelial cells are labeled in pink, podocytes are labeled in brown. Created with BioRender (https://app.biorender.com/, accessed on 14 May 2024).

Figure 3

Engineered environments that induce tissue-specific fenestrations in ECs derived from unspecialized hiPSCs. Illustration of tissue-specific EC fenestration induction via in situ development including Glomeruloid, with influences by endogenous secretion of VEGF and other currently unidentified growth factors and cytokines (top left); Glomerulus Chip, with influences by VEGF, other growth factors, and cytokines, as well as mechanical factors (e.g., shear stress) and cell-laden ECM with physiologically-relevant structure (bottom left). Illustration of tissue-specific EC fenestration induction with defined variables including 3D-scaffolds (top right), chemically-defined medium (middle right), or mechanical stress (bottom right). Created with BioRender (https://app.biorender.com/, accessed on 13 June 2024).