Daneman R, Zhou L, Kebede AA, Barres BAPericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468:562-566

UCSF Department of Anatomy, 513 Parnassus Avenue, HSW1301, San Francisco, California 94143-0452, USA.
Nature (Impact Factor: 41.46). 10/2010; 468(7323):562-6. DOI: 10.1038/nature09513
Source: PubMed


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.

Full-text preview

Available from:
  • Source
    • "Pericytes are essential for cerebral angiogenesis and endothelial barrier formation (Armulik et al., 2010; Daneman et al., 2010), which prompted us to determine if vascular pericytes were absent in Nrp1 conditional knockout mice. Immunofluorescence with anti- NG2 antibodies revealed that endothelial cells were associated with pericytes in control as well as Alk1-Cre/+;Nrp1fl/fl and 8-/-mutant mice (Supplemental Figure 5). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Angiogenesis in the developing central nervous system (CNS) is regulated by neuroepithelial cells, although the genes and pathways that couple these cells to blood vessels remain largely uncharacterized. Here, we have used biochemical, cell biological and molecular genetic approaches to demonstrate that β8 integrin and Neuropilin-1 (Nrp1) cooperatively promote CNS angiogenesis by mediating adhesion and signaling events between neuroepithelial cells and vascular endothelial cells. β8 integrin in the neuroepithelium promotes the activation of extracellular matrix (ECM)-bound latent transforming growth factor β (TGFβ) ligands and stimulates TGFβ receptor signaling in endothelial cells. Nrp1 in endothelial cells suppresses TGFβ activation and signaling by forming intercellular protein complexes with β8 integrin. Cell type-specific ablation of β8 integrin, Nrp1, or canonical TGFβ receptors results in pathological angiogenesis due to defective neuroepithelial cell-endothelial cell adhesion and imbalances in canonical TGFβ signaling. Collectively, these data identify a paracrine signaling pathway that links the neuroepithelium to blood vessels and precisely balances TGFβ signaling during cerebral angiogenesis.
    Development 11/2015; DOI:10.1242/dev.113746 · 6.46 Impact Factor
  • Source
    • "osine - b - D - arabinofuranoside has been shown to decrease the proliferation of endothelial cells and vascular permeability to blood - derived LMW molecules without changing the vascular area or diameter ( Morita et al . , 2015b ) . A recent study demonstrated that pericytes play important roles in the formation of the BBB during embryogenesis ( Daneman et al . , 2010 ) , with the loss of pericytes resulting in BBB disruption ( Armulik et al . , 2010 ) . Chronic salt loading is known to increase the pericytic expression of platelet - derived growth factor receptor ßin the sensory CVOs in combination with elevations in vascular permeability ( Morita et al . , 2014 ) . Furthermore , food and glucose de"
    [Show abstract] [Hide abstract]
    ABSTRACT: The blood–brain barrier (BBB) generally consists of endothelial tight junction barriers that prevent the free entry of blood-derived substances, thereby maintaining the extracellular environment of the brain. However, the circumventricular organs (CVOs), which are located along the midlines of the brain ventricles, lack these endothelial barriers and have fenestrated capillaries; therefore, they have a number of essential functions, including the transduction of information between the blood circulation and brain. Previous studies have demonstrated the extensive contribution of the CVOs to body fluid and thermal homeostasis, energy balance, the chemoreception of blood-derived substances, and neuroinflammation. In this review, recent advances have been discussed in fenestrated capillary characterization and dynamic tissue reconstruction accompanied by angiogenesis and neurogliogenesis in the sensory CVOs of adult brains. The sensory CVOs, including the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and area postrema (AP), have size-selective and heterogeneous vascular permeabilities. Astrocyte-/tanycyte-like neural stem cells (NSCs) sense blood- and cerebrospinal fluid-derived information through the transient receptor potential vanilloid 1, a mechanical/osmotic receptor, Toll-like receptor 4, a lipopolysaccharide receptor, and Nax, a Na-sensing Na channel. They also express tight junction proteins and densely and tightly surround mature neurons to protect them from blood-derived neurotoxic substances, indicating that the NSCs of the CVOs perform BBB functions while maintaining the capacity to differentiate into new neurons and glial cells. In addition to neurogliogenesis, the density of fenestrated capillaries is regulated by angiogenesis, which is accompanied by the active proliferation and sprouting of endothelial cells. Vascular endothelial growth factor (VEGF) signaling may be involved in angiogenesis and neurogliogenesis, both of which affect vascular permeability. Thus, recent findings advocate novel concepts for the CVOs, which have the dynamic features of vascular and parenchymal tissues.
    Frontiers in Neuroscience 10/2015; 9:390. DOI:10.3389/fnins.2015.00390 · 3.66 Impact Factor
  • Source
    • "HFs in the head skin are established perinatally, coinciding with expansion of calvarial and dermal mesenchymal cells covering the developing brain. The blood–brain barrier (BBB) matures as early as embryonic day (E) 15.5 in most forebrain areas (Daneman et al., 2010) except for a few areas, including the DG where the BBB matures postnatally. This raises a possibility that the HF stem cell niche signals interact with dermal/calvarial HSCs and the developing neurovascular units of the DG. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dentate neural stem cells produce neurons throughout life in mammals. Sonic hedgehog (Shh) is critical for maintenance of these cells; however, the perinatal source of Shh is enigmatic. In the present study, we examined the role of Shh expressed by hair follicles (HFs) that expand perinatally in temporal concordance with the proliferation of Shh-responding dentate stem cells. Specific inhibition of Shh from HFs or from epithelial sources in general hindered development of Shh-responding dentate stem cells. We also found that the blood-brain barrier (BBB) of the perinatal dentate gyrus (DG) is leaky with stem cells in the dentate exposed to blood-born factors. In attempting to identify how Shh might be transported in blood, we found that platelets contain epithelial Shh, provide Shh to the perinatal DG and that inhibition of platelet generation reduced hedgehog-responsive dentate stem cells.
    eLife Sciences 10/2015; 4. DOI:10.7554/eLife.07834 · 9.32 Impact Factor
Show more

Similar Publications