Pericyte-endothelial crosstalk: implications and opportunities for advanced cellular therapies

Abstract

Pericytes are mural cells of the microcirculation that have been shown to play key roles in regulating microvascular morphogenesis and stability throughout each tissue bed and organ system assessed. Of note, recent work has revealed that pericytes share several characteristics with mesenchymal- and adipose-derived stem cells, suggesting there may be lineage-related connections among bona fide pericytes and these vascular "progenitors," which can assume a perivascular position in association with endothelial cells. Hence, pericyte identity as a mediator of vascular remodeling may be confounded by its close relationships with its progenitors or pluripotent cell counterparts and yet demonstrates their potential utility as cell-based therapies for unmet clinical needs. Crucial to the development of such therapies is a comprehensive understanding of the origin and fate regulating these related cell types as well as the unveiling of the molecular mechanisms by which pericytes and endothelial cells communicate. Such mechanistic inputs, which disrupt normal cellular crosstalk during disease inception and progression, offer opportunities for intervention and are discussed in the context of the vasculopathies accompanying tumor growth, diabetes, and fibrosis.

Figure 1. Discriminating between vascular cells using contractile protein isoform-specific antibodies

Co-cultures of mural cells and vascular endothelial cells were fixed and permeabilized before labeling with anti-vascular smooth muscle actin-specific IgG. Note the brightly fluorescent mural cells with robust stress fibers and the darkened (negative) image of the endothelial cell (*)‘draping’ across the pericyte.

Figure 2. In situ localization of a mural cell-enriched cerebral microvessel

Frozen rat brain sections were prepared from perfusion-fixed specimens prior to treatment with fluorescently-labeled anti-smooth muscle actin IgG. Note the abundance of antibody-stained mural cells aligned along the length of this ‘muscular’ venule.

Figure 3. The pericyte cohort: Characterization of molecular marker profiles of stellate cells, mesangial cells, MSCs, ASCs, and pericytes

The Venn Diagram above compares molecular markers expressed by stellate cells, mesangial cells, MSCs, ASCs, and pericytes. These markers are important in several important signaling pathways such as adhesion, receptor-ligand binding, and extracellular matrix formation. The similarities in function and marker profile between these cells support the notion that they are related and comprise a family or “cohort” of cells. As discussed, this cohort is comprised of mural cells (pericytes and vascular smooth muscle cells), perivascular cells (adipose- and mesenchymal-derived stem cells), and interstitial myofibroblast-like cells (mesangial and stellate cells). Note: This diagram does not portray all molecular markers expressed by these cell types, and is reviewed elsewhere (28, 33, 48, 54).