Regenerative Medicine: The Hurdles and Hopes
Review Article
Pericyte-endothelial crosstalk: implications and opportunities for advanced cellular therapies

https://doi.org/10.1016/j.trsl.2014.01.011Get rights and content

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.

Section snippets

Pericytes and Microvascular Remodeling

During vascular remodeling, the blood vessel responds to hemodynamic changes to adapt and restore homeostasis. Endothelial cells comprise the inner lining of vessels whereas pericytes encompass blood microvessels such as blood capillaries, precapillary arterioles, precapillary venules, and collecting venules.1 Pericytes use cytoplasmic processes to surround the abluminal surface of the endothelial tube.2 They share and coproduce a basement membrane with endothelial cells, demonstrating that

Evolution of the Pericyte in History

Pericytes were first described by Charles-Marie Benjamin Rouget in 1873 as cells with contractile properties that surround the endothelial cells of small blood vessels.1 Krogh investigated capillary recruitment and vascular tone further and defined the cells adjacent to the endothelium that may be involved in these functions as Rouget cells. By 1923, Zimmermann devised the term “pericyte” because of the cell's close proximity to endothelial cells, and used light microscopy studies to elucidate

Pericyte Origin

Pericytes were first evidenced by Clark and Clark11 in 1925, who observed the development of pericytes on the capillaries of tadpole larvae from connective tissue components. Lineage tracing studies using chick-quail chimeras and cell-specific markers later demonstrated that a majority of pericytes found in the cephalic region and central nervous system was derived from the neural crest.12, 13 Fate mapping analyses in mice using genetic reporters have also shown that cells from the mesothelium

Pericyte-Endothelial Cell Ratios Vary across Tissues

The number and size of pericyte-endothelial contacts varies considerably in different tissues and in vessels of differing size. In general, pericytes are more abundant and have more extensive processes in venous capillaries and postcapillary venules.1, 2 Endothelial-to-pericyte ratios in normal tissues vary between 1:1 and 10:1, whereas pericyte coverage of the endothelial abluminal surface ranges between 70% and 10%.1, 2 The highest density of pericytes (endothelial cell-to-pericyte ratio,

Molecular Mediators of Vascular Remodeling and Stability Are Dependent on Endothelial Cell-Pericyte Interactions

Because variations in pericyte density can alter the microenvironment of the vasculature, soluble mediators synthesized or expressed by vascular and nonvascular cells facilitate remodeling through coordinated endothelial-pericyte interactions. Several key entities involved in coordinating endothelial-pericyte signaling are discussed in the following paragraphs.

Pericyte Markers Corroborate Ambiguity in Pericyte Characterization

Identification of pericytes within the microvasculature has been critical to the elucidation of pericyte-endothelial crosstalk. Pericytes express a wide variety of molecular markers, suggesting they may comprise, give rise to, or descend from a diverse population of progenitor or murallike cells.1 Accurate identification of pericytes and this “cohort” of vascular cells is dependent both on surface marker expression profiles and a “mapping” of their location along the abluminal surface of

Stellate Cell: The Pericyte Cell of the Liver

Stellate cells have been long regarded as specialized pericytes of the liver and are characterized by droplets of vitamin A found in their cytoplasm. Comprising about 5%–8% of total cells in the normal liver, these desmin- and PDGFR-β-positive cells are located in the perisinusoidal space, between the fenestrated endothelium.26 Believed to regulate microvascular hepatic flow, stellate cells foster sinusoidal constriction and are therefore a possible therapeutic target for portal hypertension.27

The Mesangial Cell: A Renal Pericyte?

Although the stellate cell is the matrix-producing pericyte of the liver, the mesangial cell is its cellular counterpart in the kidney. Mesangial cells can be considered a specialized subset of pericytes located in the glomerulus, whereas pericytes found in the tubular interstitium are referred to as “peritubular pericytes.”32 Mesangial cells express PDGFR-β and exhibit contractile properties and a cytoskeletal architecture that anchors filaments to the glomerular basement membrane opposing

The Pericyte-Mesenchymal Stem Cell Conundrum

Although there is general agreement in the literature that stellate cells and mesangial cells are related embryologically and functionally to microvascular pericytes, there is much controversy regarding whether pericytes are descendants or antecedents of MSCs. Dar et al35 demonstrated recently that differentiating human pluripotent stem cells could give rise to pericytes. They identified a population of CD31-CD73+CD90+CD105+ cells that expressed pericyte markers such as NG2, CD146, and PDGFR-β

ASCs Exhibit Pericyte Phenotype

Although MSCs are excellent candidates for use in regenerative medicine, they are both more difficult to isolate and represent a small fraction of cells in the adult hematopoietic system. In contrast, ASCs are abundant and are extracted easily from a stromal vascular fraction from adipose tissue. Immunofluorescence and flow cytometry studies show that the majority of processed lipoaspirate from human tissue is of mesodermal or mesenchymal origin. In addition, ASCs are capable of differentiating

Role of Pericyte-Endothelial Cell Interactions in Disease

Aberrations in pericyte-endothelial cell interactions are a possible focal point wherein microvascular dysfunction and vasculopathy accompanying disease progression may originate. As discussed later, perturbations in endothelial-pericyte signaling may indeed represent a key mechanism by which the microvasculature becomes dysregulated, unstable, and ultimately pathogenic in such disease states such as diabetes, fibrosis, and cancer.

Conclusion: Pericytes as Potential Targets in Cellular Therapy

Pericytes play a fundamental role in the remodeling and stability of the vasculature. Although definitive pericyte characterization within various tissues and organ systems remains incomplete, these mural or perivascular cells represent key microvascular components. The mesangial cell and hepatic stellate cell are specialized pericytes of the kidney and liver, respectively, and can become myofibroblastlike. When considering the perivascular basis of the stem cell niche, MSCs and ASCs share

Acknowledgments

Conflicts of Interest: The authors have read the journal's policy on potential conflicts of interest and have none to declare.

This work was supported by the following grants: National Institutes of Health EY 15125 and EY 022063 (IMH).

The authors are grateful to Dr Tatiana Demidova-Rice and Dr Jennifer Durham for their critical reading of this manuscript.

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