‘Sealing off the CNS’: cellular and molecular regulation of blood–brain barriergenesis

https://doi.org/10.1016/j.conb.2013.06.006Get rights and content

Highlights

  • We review the multi-faceted process of blood–brain barriergenesis.

  • We outline the different properties of the BBB and temporal order of appearance.

  • Focus on cellular contribution to barriergenesis events, namely pericytes and astrocytes.

  • Review neural-derived signals, like Wnt ligands, that promote barrier properties.

From their initial ingression into the neural tube to the established, adult vascular plexus, blood vessels within the CNS are truly unique. Covered by a virtually continuous layer of perivascular cells and astrocytic endfeet and connected by specialized cell–cell junctional contacts, mature CNS blood vessels simultaneously provide nutritive blood flow and protect the neural milieu from potentially disruptive or harmful molecules and cells flowing through the vessel lumen. In this review we will discuss how the CNS vasculature acquires blood–brain barrier (BBB) properties with a specific focus on recent work identifying the cell types and molecular pathways that orchestrate barriergenesis.

Section snippets

Cellular regulation of barriergenesis: pericytes

Pericytes are an important perivascular cell type related to vascular smooth muscle cells (vSMCs) and are largely defined by their location with the vascular plexus (small-diameter capillaries) and close interaction with endothelial cells [10]. Pericytes are found at high density in CNS vasculature and their important role in neurovascular development is underscored by mouse models of pericyte-deficiency caused by genetic disruption of platelet-derived growth factor-B (PDGFB) signaling [11, 12•

Cellular regulation of barriergenesis: astrocytes

In the latter half of gestation in human development [22] and soon after birth in mice [3••], astrocytic processes or endfeet ensheath the brain endothelium and, in this position, they are poised to aid in the maturation and maintenance of the BBB. Evidence of a role for astrocytes in barrier maturation is based on several in vitro studies showing that either co-culture with astrocytes or astrocyte-conditioned media induces BBB properties in cultured endothelial cells, specifically increased

Molecular regulation of barriergenesis

Although it is clear that pericytes and astrocytes can regualte barrier properties during development and adulthood, many important BBB-specific properties appear to be under control of embryonic neural progenitors. The appearance of specialized TJs and the expression of transporters are important events in barriegenesis that arise in the absence of pericytes and before astrocyte generation, and likely depend on neural progenitor-derived signals. Indeed, in vitro cell culture experiments have

Concluding remarks

The complexity of signals involved in blood brain barriergenesis not only reflects the different properties of the BBB but also the temporal acquisition of these properties during prenatal and postnatal brain development. Expression of different transporters, accumulation of TJ structures and proteins and decline in LAMs are not instantaneous events as blood vessels enter neural tissue. The induction of these properties appears to be orchestrated by a series of different cellular interactions

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (47)

  • S.J. Tam et al.

    Death receptors DR6 and TROY regulate brain vascular development

    Dev Cell

    (2012)
  • H. Li et al.

    A retinoic acid synthesizing enzyme in ventral retina and telencephalon of the embryonic mouse

    Mech Dev

    (2000)
  • R. Daneman et al.

    Pericytes are required for blood–brain barrier integrity during embryogenesis

    Nature

    (2010)
  • T. Nakao et al.

    Observations of vascularization in the spinal cord of mouse embryos, with special reference to development of boundary membranes and perivascular spaces

    Anat Rec

    (1988)
  • S. Wakai et al.

    Development of the blood–brain barrier to horseradish peroxidase in the chick embryo

    Cell Tissue Res

    (1978)
  • W. Risau et al.

    Brain induces the expression of an early cell surface marker for blood–brain barrier-specific endothelium

    EMBO J

    (1986)
  • A.M. Butt et al.

    Electrical resistance across the blood–brain barrier in anaesthetized rats: a developmental study

    J Physiol

    (1990)
  • U. Kniesel et al.

    Development of blood–brain barrier tight junctions in the rat cortex

    Brain Res Dev Brain Res

    (1996)
  • P. Lindahl et al.

    Pericyte loss and microaneurysm formation in PDGF-B-deficient mice

    Science

    (1997)
  • M. Hellström et al.

    Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse

    Development

    (1999)
  • C.J. Dente et al.

    Pericytes augment the capillary barrier in in vitro cocultures

    J Surg Res

    (2001)
  • S. Dohgu et al.

    Brain pericytes contribute to the induction and up-regulation of blood–brain barrier functions through transforming growth factor-beta production

    Brain Res

    (2005)
  • B.V. Zlokovic

    Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders

    Nat Rev Neurosci

    (2011)
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      Citation Excerpt :

      The BBB is surrounded by or closely associated with other cell types in the NVUs, including neurons, microglia, and, optionally, blood-borne immune cell populations that also contribute to the modulation of BBB functions [4]. BBB formation in mammals initiates at the early embryonic period when endothelial progenitor cells enter the cortex and vascularize the CNS [5]. The exact timing is species-dependent and varies regionally.

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