Regenerative Medicine: The Hurdles and HopesReview ArticlePericyte-endothelial crosstalk: implications and opportunities for advanced cellular therapies
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.
References (75)
- et al.
Pericytes: developmental, physiological, and pathological perspectives, problems, and promises
Dev Cell
(2011) The pericyte: a review
Tissue Cell
(1986)- et al.
Pericytes and vascular stability
Exp Cell Res
(2006) - et al.
TGF-β 1 signaling controls retinal pericyte contractile protein expression
Microvasc Res
(2003) - et al.
Pericyte Rho GTPase mediates both pericyte contractile phenotype and capillary endothelial growth state
Am J Pathol
(2007) - et al.
The pericyte: cellular regulator of microvascular blood flow
Microvasc Res
(2009) Insight into the physiological functions of PDGF through genetic studies in mice
Cytokine Growth Factor Rev
(2004)- et al.
Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival
Dev Biol
(2003) - et al.
Hepatic stellate cell: a star cell in the liver
Int J Biochem Cell Biol
(2009) - et al.
The myofibroblast: one function, multiple origins
Am J Pathol
(2007)