Understanding the Heterogeneity of Human Pericyte Subsets in Blood-Brain Barrier Homeostasis and Neurological Diseases

Abstract

Pericytes are increasingly recognized as being important in the control of blood-brain barrier permeability and vascular flow. Research on this important cell type has been hindered by widespread confusion regarding the phenotypic identity and nomenclature of pericytes and other perivascular cell types. In addition, pericyte heterogeneity and mouse-human species differences have contributed to confusion. Herein we summarize our present knowledge on the identification of pericytes and pericyte subsets in humans, primarily focusing on recent findings in humans and nonhuman primates. Precise identification and definition of pericytes and pericyte subsets in humans may help us to better understand pericyte biology and develop new therapeutic approaches specifically targeting disease-associated pericyte subsets.

Keywords: Alzheimer’s disease; blood–brain barrier; endothelial cell; laminin; multiple sclerosis; pericyte; perivascular macrophage; sonic hedgehog; vascular smooth muscle cell.

Figure 1

Luxol fast blue staining of a formalin-fixed paraffin-embedded corpus callosum tissue section, from a middle-aged female multiple sclerosis patient (obtained as de-identified from a commercial source, BioChain, Newark, California), shows a demyelinating lesion which is circled with a dashed line (A). A serial section was then stained with anti-PDGFRB-AF488, anti-SMA-AF647, anti-laminin-111/211-BV480 and anti-myelin-Cy3, and was examined under confocal microscopy. The number of PC1- and PC2-associated vessels were counted in five lesion and five NAWM frames at 40x and the %PC2 was calculated and indicated that there was a higher %PC2 in the lesion than NAWM (B). Regions of interest (ROIs) were established by outlining the PC1- and PC2-associated vessels from five 40x frames within the lesion and NAWM. The MPIs of laminin-111/211 and myelin staining were quantified in each ROI using NIH ImageJ to determine that PC2-associated vessels correlated with lower laminin-111/211 and myelin than PC1-associated vessels regardless of lesion association (C,D). A correlation between the laminin-111/211 and myelin MPIs between each ROI showed that there was a strong positive correlation between laminin-111/211 and myelin and that PC2-associated vessels fell only on the low end of that association (E). Graphs with statistical analysis were generated using GraphPad Prism: * = p < 0.05, ** = p < 0.01.