ECM in the central nervous system
To understand the role of the cellular microenvironment in neural functions and neuropathology, we study
the organization, functions, and malignant changes of the
extracellular matrix
(ECM) in the central nervous system.
The neural ECM is a scaffold that fills the intercellular spaces in the brain and spinal cord, forming the immediate support and environment of neurons and glial cells. Its relevance in neural functions (and even its existence!) was dismissed until the beginning of the ‘80s because of technical difficulties to visualize and analyze it, but today the neural ECM is recognized as a major structural and functional component of the central nervous system. The intercellular space occupied by this matrix fills up as much as 20% of the adult brain volume. Matrix molecules are known to regulate most neural processes, including cell migration, axonal extension, formation of synapses, and synaptic plasticity.
A glial cell in culture (red) surrounded by a pericellular coat of hyaluronic acid (blue) that extends beyond the cell membrane (black dots) and keeps other particles separated from the cell (© Viapiano Lab).
ECM functions
During development, the neural ECM is highly elastic and soluble, facilitating cell division and migration throughout the brain. In the adult nervous system, this matrix becomes a condensed foam-like
scaffold around cells and restricts further movement of cells and axons, thus becoming a major barrier for
cellular motility and for the formation of new synaptic connections.
This inhibitory effect is attributed mostly to the accumulation of matrix components such as hyaluronic acid and chondroitin sulfate proteoglycans -CSPGs- (see ECM molecules), forming insoluble aggreagates. The inhibitory role of the CSPGs has been observed in
many in vitro and in vivo models; these molecules inhibit the formation of synaptic
contacts and act as chemorepellents for motile cells and axons. They are among the major components
upregulated in the glial scar that forms after injury, preventing neuroregeneration. Enzymatic degradation of
hyaluronic acid and chondroitin sulfate removes the inhibitory ECM scaffold in the adult CNS; this can
partially recover the ability of axons to extend through damaged tissue, and can also renew synaptic
plasticity in adult neural circuits.
Interestingly, malignant brain tumors are known to produce large amounts of CSPGs, but these molecules
do not play any inhibitory role in the tumor and, in fact, increase tumor invasion of normal brain tissue.
The mechanisms by which CSPGs and other matrix molecules act in such surprising, "pro-motility" fashion in
brain cancer is one of the major aspects of our research.
Axons that extend from a neural explant towards an attractant (upper right) can be repelled by neural proteoglycans in culture
(image courtesy of Dr. Diego Rodriguez-Gil, Dept. Neurosurgery Yale University).
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