Pericytes are required for blood–brain barrier integrity during embryogenesis
TL;DR: Pericytes regulate functional aspects of the blood–brain barrier, including the formation of tight junctions and vesicle trafficking in CNS endothelial cells, but inhibit the expression of molecules that increase vascular permeability and CNS immune cell infiltration.
Abstract: Vascular endothelial cells in the central nervous system (CNS) form a barrier that restricts the movement of molecules and ions between the blood and the brain. This blood-brain barrier (BBB) is crucial to ensure proper neuronal function and protect the CNS from injury and disease. Transplantation studies have demonstrated that the BBB is not intrinsic to the endothelial cells, but is induced by interactions with the neural cells. Owing to the close spatial relationship between astrocytes and endothelial cells, it has been hypothesized that astrocytes induce this critical barrier postnatally, but the timing of BBB formation has been controversial. Here we demonstrate that the barrier is formed during embryogenesis as endothelial cells invade the CNS and pericytes are recruited to the nascent vessels, over a week before astrocyte generation. Analysing mice with null and hypomorphic alleles of Pdgfrb, which have defects in pericyte generation, we demonstrate that pericytes are necessary for the formation of the BBB, and that absolute pericyte coverage determines relative vascular permeability. We demonstrate that pericytes regulate functional aspects of the BBB, including the formation of tight junctions and vesicle trafficking in CNS endothelial cells. Pericytes do not induce BBB-specific gene expression in CNS endothelial cells, but inhibit the expression of molecules that increase vascular permeability and CNS immune cell infiltration. These data indicate that pericyte-endothelial cell interactions are critical to regulate the BBB during development, and disruption of these interactions may lead to BBB dysfunction and neuroinflammation during CNS injury and disease.
Citations
More filters
TL;DR: Mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, are examined, and therapeutic opportunities relating to these neurovascular deficits are highlighted.
Abstract: The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood-brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal 'milieu', which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, and highlights therapeutic opportunities relating to these neurovascular deficits.
2,256 citations
TL;DR: The history of investigations into pericytes, the mural cells of blood microvessels, are reviewed, emerging concepts are indicated, and problems and promise are pointed out.
2,120 citations
Cites background from "Pericytes are required for blood–br..."
...Other reports implicate pericytes in the regulation of T cell exit from the thymus (Zachariah and Cyster, 2010) and in the regulation of leukocyte adhesion molecules in endothelial cells (Daneman et al., 2010) (discussed above)....
[...]
...…blood vessels identified several deregulated genes previously implicated in the regulation of endothelial permeability, including vegfa, ang2, and adrenomedullin (all up in the pericyte-deficient state) and ang1 (down in the pericyte-deficient state) (Armulik et al., 2010; Daneman et al., 2010)....
[...]
...Two recent studies addressing the role of pericytes in the brain vasculature challenge the ‘‘in vitro view’’ of pericytes regulating the permeability of endothelial cell-cell junctions (Armulik et al., 2010; Daneman et al., 2010)....
[...]
...Recent work has uncovered a critical role for pericytes in the maturation and maintenance of the BBB (Armulik et al., 2010; Bell et al., 2010; Daneman et al., 2010)....
[...]
...One of the studies, performed in a neurobiology lab (Daneman et al., 2010), asked which cell types are important for the development of the BBB during embryogenesis....
[...]
TL;DR: Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.
Abstract: Blood vessels are critical to deliver oxygen and nutrients to all of the tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, and alterations of these barrier properties are an important component of pathology and progression of different neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the endothelial cells (ECs) that form the walls of the blood vessels, and these properties are regulated by interactions with different vascular, immune, and neural cells. Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.
1,839 citations
Cites background from "Pericytes are required for blood–br..."
...Comparative microarray analysis has identified that effectors of Wnt/b-catenin signaling, including Lef1, Apcdd1, and tnfrsf19, are enriched CNS ECs compared to ECs in peripheral organs (Daneman et al. 2009, 2010a)....
[...]
...In particular, lack of PCs leads to an increase in the rate of transcytosis and an increase in the expression of LAMs resulting in CNS-immune infiltration (Armulik et al. 2010; Daneman et al. 2010b)....
[...]
...…genes involved in BBB-specific properties, such as tight junctions, nutrient transport, or efflux transport, but an increase in the expression of genes involved in peripheral EC-specific “leaky” properties, including transcytosis (PLVAP) and leukocyte adhesion (Icam1, Alcam) (Daneman et al. 2010b)....
[...]
...Further use of mice with Pdgfrb hypomorphic alleles, which have varying numbers of CNS PCs, showed that the total number is important for the relative permeability of the vessels (Armulik et al. 2010; Daneman et al. 2010b)....
[...]
...In addition, these cells have been shown to be important for regulating the formation of the BBB during development, as well as maintaining its function in adulthood and aging (Armulik et al. 2010; Daneman et al. 2010b)....
[...]
TL;DR: This Review highlights recently gained mechanistic insights into the development and maintenance of the blood-brain barrier (BBB), and discusses how BBB disruption can cause or contribute to neurological disease.
Abstract: The interface between the blood circulation and the neural tissue features unique characteristics that are encompassed by the term 'blood-brain barrier' (BBB). The main functions of this barrier, namely maintenance of brain homeostasis, regulation of influx and efflux transport, and protection from harm, are determined by its specialized multicellular structure. Every constituent cell type makes an indispensable contribution to the BBB's integrity. But if one member of the BBB fails, and as a result the barrier breaks down, there can be dramatic consequences and neuroinflammation and neurodegeneration can occur. In this Review, we highlight recently gained mechanistic insights into the development and maintenance of the BBB. We then discuss how BBB disruption can cause or contribute to neurological disease. Finally, we examine how this knowledge can be used to explore new possibilities for BBB repair.
1,616 citations
TL;DR: This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy.
Abstract: The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented
1,507 citations
References
More filters
TL;DR: These findings call into question the concept of a “glial” cell class as the gene profiles of astrocyte and oligodendrocytes are as dissimilar to each other as they are to neurons, for better understanding of neural development, function, and disease.
Abstract: Understanding the cell–cell interactions that control CNS development and function has long been limited by the lack of methods to cleanly separate neural cell types. Here we describe methods for the prospective isolation and purification of astrocytes, neurons, and oligodendrocytes from developing and mature mouse forebrain. We used FACS (fluorescent-activated cell sorting) to isolate astrocytes from transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of an S100β promoter. Using Affymetrix GeneChip Arrays, we then created a transcriptome database of the expression levels of >20,000 genes by gene profiling these three main CNS neural cell types at various postnatal ages between postnatal day 1 (P1) and P30. This database provides a detailed global characterization and comparison of the genes expressed by acutely isolated astrocytes, neurons, and oligodendrocytes. We found that Aldh1L1 is a highly specific antigenic marker for astrocytes with a substantially broader pattern of astrocyte expression than the traditional astrocyte marker GFAP. Astrocytes were enriched in specific metabolic and lipid synthetic pathways, as well as the draper/Megf10 and Mertk/integrin αvβ5 phagocytic pathways suggesting that astrocytes are professional phagocytes. Our findings call into question the concept of a “glial” cell class as the gene profiles of astrocytes and oligodendrocytes are as dissimilar to each other as they are to neurons. This transcriptome database of acutely isolated purified astrocytes, neurons, and oligodendrocytes provides a resource to the neuroscience community by providing improved cell-type-specific markers and for better understanding of neural development, function, and disease.
2,838 citations
TL;DR: These findings support developments of new therapeutic approaches for chronic neurodegenerative disorders directed at the blood-brain barrier and other nonneuronal cells of the neurovascular unit.
2,797 citations
TL;DR: Comparisons made between PDGF null mouse phenotypes suggest a general role for PDGFs in the development of myofibroblasts, and endothelial cells of the sprouting capillaries in the mutant mice appeared to be unable to attract PDGF-Rbeta-positive pericyte progenitor cells.
Abstract: Platelet-derived growth factor (PDGF)-B-deficient mouse embryos were found to lack microvascular pericytes, which normally form part of the capillary wall, and they developed numerous capillary microaneurysms that ruptured at late gestation. Endothelial cells of the sprouting capillaries in the mutant mice appeared to be unable to attract PDGF-Rbeta-positive pericyte progenitor cells. Pericytes may contribute to the mechanical stability of the capillary wall. Comparisons made between PDGF null mouse phenotypes suggest a general role for PDGFs in the development of myofibroblasts.
2,127 citations
TL;DR: Direct evidence is provided that astrocytes are capable of inducing blood–brain barrier properties in non-neural endothelial cells in vivo.
Abstract: The highly impermeable tight junctions between endothelial cells forming the capillaries and venules in the central nervous system (CNS) of higher vertebrates are thought to be responsible for the blood-brain barrier that impedes the passive diffusion of solutes from the blood into the extracellular space of the CNS. The ability of CNS endothelial cells to form a blood-brain barrier is not intrinsic to these cells but instead is induced by the CNS environment: Stewart and Wiley demonstrated that when avascular tissue from 3-day-old quail brain is transplanted into the coelomic cavity of chick embryos, the chick endothelial cells that vascularize the quail brain grafts form a competent blood-brain barrier; on the other hand, when avascular embryonic quail coelomic grafts are transplanted into embryonic chick brain, the chick endothelial cells that invade the mesenchymal tissue grafts form leaky capillaries and venules. It is, however, not known which cells in the CNS are responsible for inducing endothelial cells to form the tight junctions characteristic of the blood-brain barrier. Astrocytes are the most likely candidates since their processes form endfeet that collectively surround CNS microvessels. In this report we provide direct evidence that astrocytes are capable of inducing blood-brain barrier properties in non-neural endothelial cells in vivo.
1,454 citations
TL;DR: These findings show that genetic targeting can be used to ablate scar-forming astrocytes and demonstrate roles for astroCytes in regulating leukocyte trafficking, repairing the BBB, protecting neurons, and restricting nerve fiber growth after injury in the adult central nervous system.
1,051 citations