It has been suggested that a vascular-like cell has multipotent regenerative and mesenchymal lineage relationships. The identity of this stem/progenitor cell has remained elusive. We report here that adult central nervous system (CNS) capillaries contain a distinct population of microvascular cells, the pericyte that are nestin/NG2 positive and in response to basic fibroblast growth factor (bFGF) differentiate into cells of neural lineage. In their microvascular location, pericytes express nestin and NG2 proteoglycan. In serum containing media primary (0 to 7 day old) CNS pericytes are nestin positive, NG2 positive, alpha smooth muscle actin (alphaSMA) positive, and do not bind the endothelial cell specific griffonia symplicifolia agglutinin (GSA). In serum containing media, pericytes do not undergo neurogenesis but are induced to express alphaSMA. In bFGF containing media without serum, CNS pericytes form small clusters and multicellular spheres. Differentiated spheres expressed neuronal and glial cell markers. After disruption and serial dilution, differentiated spheres were capable of self-renewal. When differentiated spheres were disrupted and cultured in the presence of serum, multiple adherent cell populations were identified by dual and triple immunocytochemistry. Cells expressing markers characteristic of pericytes, neurons, and glial cells were generated. Many of the cells exhibited dual expression of differentiation markers. With prolonged culture fully differentiated cells of neural lineage were present. Results indicate that adult CNS microvascular pericytes have neural stem cell capability.

Pericytes were described nearly 140 years ago by the French scientist Charles-Marie Benjamin Rouget and were referred to as the Rouget cell. The Rouget cell was renamed primarily due to its anatomical location in the endothelium. Pericytes are important cellular constituents of the capillaries and post capillary venules and are located abluminal to the endothelial cells and luminal to parenchymal cells. They deposit elements of the basal lamina and are totally surrounded by this vascular component. Despite many years of investigation since their discovery, the role of this intriguing cell still remains a mystery, in part, due to the difficulty of studying this cell in vivo, due to the difficulty of isolating pure primary pericytes, and due to the lack of a pericyte specific marker. Pericytes are thought to be local regulatory cells and important to the maintenance of homeostasis and hemostasis. In the brain, pericytes are in active communication with the cells of the neurovascular unit and make fine-tuned regulatory adjustments in response to stress stimuli. These adaptations at the vascular level form the basis for functional and phenotypic changes that include differentiation along mesenchymal and neurological lineages, and lend credence to the supposition that pericytes are multipotential stems cells in the adult brain and in other tissues. This review will consider evidence that pericytes are stem cells derived from historical work and from more recent literature, and will attempt to dispel a number of misconceptions about the pericyte that has lead to confusion in the literature. We will also speculate on the importance of pericyte stem cell activity in survival and DNA repair and how dysregulation of pericyte function may lead to disease.

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Pericytes are a very important cellular constituent of the blood-brain barrier. They play a regulatory role in brain angiogenesis, endothelial cell tight junction formation, blood-brain barrier differentiation, as well as contribute to the microvascular vasodynamic capacity and structural stability. Central nervous system pericytes express macrophage functions and are actively involved in the neuroimmune network operating at the blood-brain barrier. They exhibit unique functional characteristics critical for the pathogenesis of a number of cerebrovascular, neurodegenerative, and neuroimmune diseases.

Hypoxic acclimatization includes increased brain capillary density. Adaptive angiogenesis, which occurs over a 3-week period, is mediated by upregulation of vascular endothelial growth factor induced by hypoxia-inducible factor-1 in concert with the capillary remodeling molecule angiopoietin-2, which is upregulated through cyclooxygenase-2 production of prostaglandin E2. The process is apparently orchestrated by pericytes, which regulate the microvascular milieu and coordinate the interactions within the neurovascular unit. The return to normoxia is accompanied by microvascular regression and decreasing numbers of capillaries to prehypoxic densities. Regression is the result of endothelial cell apoptosis, suggesting the existence of physiologic mechanisms for adjusting capillary density to balance oxygen availability and oxygen consumption. The capacity for adaptation is diminished in older rats because of the attenuation of the hypoxia-inducible factor-1 response.

Pericytes were described in 1873 by the French scientist Charles-Marie Benjamin Rouget and were originally called Rouget cells. The Rouget cell was renamed some years later due to its anatomical location abluminal to the endothelial cell (EC) and luminal to parenchymal cells. In the brain, pericytes are located in precapillary arterioles, capillaries and postcapillary venules. They deposit elements of the basal lamina and are totally surrounded by this vascular component. Pericytes are important cellular constituents of the blood-brain barrier (BBB) and actively communicate with other cells of the neurovascular unit such as ECs, astrocytes, and neurons. Pericytes are local regulatory cells that are important for the maintenance of homeostasis and hemostasis, and are a source of adult pluripotent stem cells. Further understanding of the role played by this intriguing cell may lead to novel targeted therapies for neurovascular diseases.

The French scientist Charles Benjamin Rouget identified the pericyte nearly 140 years ago. Since that time the role of the pericyte in vascular function has been difficult to elucidate. It was not until the development of techniques to isolate and culture pericytes that scientists have begun to understand the true impact of this unique cell in the maintenance of tissue homeostasis. In the brain the pericyte is an integral cellular component of the blood-brain barrier and, together with other cells of the neurovascular unit (endothelial cells, astrocytes and neurons) the pericyte makes fine-tuned regulatory adjustments and adaptations to promote tissue survival. These regulatory changes involve trans-cellular communication networks between cells. In this review we consider evidence for cell-to-cell crosstalk between pericytes and astrocytes during development and in adult brain.

The extracellular matrix (ECM) is an important regulator of angiogenesis and vascular remodeling. We showed previously that angiogenic capillaries in the developing CNS express high levels of fibronectin and its receptor α5β1 integrin, and that this expression is developmentally downregulated. As cerebral hypoxia leads to an angiogenic response, we sought to determine whether angiogenic vessels in the adult CNS re-express fibronectin and the α5β1 integrin. Ten-week old mice were subject to hypobaric hypoxia for 0, 4, 7 and 14 days, and fibronectin/integrin expression examined. Fibronectin and the α5 integrin subunit were strongly upregulated on capillaries in the hypoxic CNS, with the effect maximal at the earliest time point examined (4 days). Immunofluorescent studies demonstrated that the α5 integrin was expressed by angiogenic endothelial cells. In light of the defined angiogenic role for fibronectin in other systems, this work suggests that induction of fibronectin-α5β1 integrin expression may be an important molecular switch driving angiogenesis in the hypoxic CNS.