Brain Barriers  - Development and Stem Cells

Embryonic Development of the Brain Barriers:

In the neurovascular (NVU) unit of the blood brain barrier (BBB), the endothelial cells of the perineural vascular plexus develop tight junctions between embryonic days E11 and E13. Even at early stages of development, pericytes are associated with the endothelial cells, and are required for vessel maturation.

The polarized epithelial cells of the choroid plexus (ChP) differentiate from the ependymal cells lining the ventricular walls. The basal surface of the ChP epithelial cells faces the stroma, whereas the apical surface extends microvilli into the CSF-filled ventricles.  In mice, ChP development begins at E11.

The third barrier, the meninges, is formed of two layers: the pachymeninges or dura mater, and the leptomeninges, which is made up of the arachnoid mater and pia mater. The subarachnoid space is located between the arachnoid and the pia mater and contains delicate trabeculae and cerebrospinal fluid (CSF). In the trunk and caudal regions of the head, the meninges originate from paraxial mesenchyme, while the meninges from the skull anterior to the mid-brain are derived from cranial neural crest cells (arising from the posterior diencephalic neural crest cells). The pia mater on the surface of the spinal cord and brain is seen already on day 24 of human embryonic development, while the dura mater can be seen in the basal areas by day 41. The arachnoid mater separates from the dura mater by the end of the embryonic development, by day 57. 

Anatomical Structure of the Brain Barriers:

The blood-brain barrier (BBB) is a vascular barrier between the systemic blood circulation and the fluids of the central nervous system (CNS). The neurovascular (NVU) unit of the BBB is the barrier that forms between the blood and brain, at the cerebrovascular interface, and requires the presence of pericytes, astrocytes and microglia cells that surround the endothelial cells of the blood vessels.

The blood-cerebrospinal fluid barrier (BCSFB) is formed by the epithelial cells of the choroid plexus, which face the cerebrospinal fluid (CSF). The third interface of the BBB is typically referred to as the meningeal barrier, and is formed between the CSF-filled subarachnoid space (SAS) and the overlying structures, by the cells of the arachnoid layer which lie between these two regions.

In the embryo, the fetal CSF-brain barrier is a temporary barrier between the CSF and brain parenchyma which is formed by a physical barrier of neuroependymal cells which are arranged between the CSF and the brain interstitial space. In the adult, these cells have transformed to the layer of non-dividing ependymal cells and there is free exchange between the CSF and the extracellular space of the brain.

Functions of the Brain Barriers:

A fundamental diffusion barrier exists at all the BBB interfaces, and is enabled by tight junctions that form between the cells of the interface. These tight junctions provide the basis for selectivity of barrier interfaces and primarily exclude hydrophilic proteins and other large molecules. Smaller molecules appear in CSF and brain, in both adult and immature animals, in proportion to their molecular size/diffusion coefficients.