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Stem cell migration: Your brain on (polysialic) acid

Immunostaining of three proteins present on differentiated neural stem cells (A, PSA-NCAM; B, glial fibrillary acidic protein; C, tubulin beta II) and triple-colored immunofluorescence showing similar distribution of PSA-NCAM and tubulin (D).

The neural cell adhesion molecule (NCAM) is a transmembrane protein that influences the development and migration of neuronal and glial cells. NCAM is functionally modified through the attachment of polysialic acid (PSA) — a negatively charged carbohydrate polymer consisting of 20-100 sialic acid molecules that is synthesized by the sialyltransferase STX. Work has been carried out on the link between PSA and neurotransmission (see here). Now, two new studies shed more light on the functional consequences of the PSA modification for stem cell migraion in the brain.

In a report to Stem Cells, Glaser et al. examined the migration of genetically modified embryonic stem cell-derived glial precursor cells (ESGPs) that expressed densely polysialylated NCAM molecules (PSA⁺-ESGPs). Using an in vitro migration assay, the authors observed a five-fold increase in the migration capacity of PSA⁺-ESGPs when compared to normal ESGPs. PSA⁺-ESGPs also invaded rat hippocampal explants to a greater extent than their normal counterparts. These findings were extended to embryonic stem cell-derived neuronal precursors, indicating that polysialylation of NCAM increases the migratory potential of brain cells.

Chemoattractant gradients provide directional cues for neural cell migration, and the authors found that overexpression of PSA enhanced ESGP migration towards the platelet-derived growth factor (PDGF) chemoattractant in vitro. This effect was also observed in vivo with EGSPs that were transplanted into the adult striatum. PSA⁺-ESGPs, but not normal ESGPs, displayed targeted migration towards the subventricular zone (SVZ), the center of brain stem cell production in the adult. Furthermore, the use of specific pathway inhibitors showed that the chemotactic response of PSA⁺-ESGPs depends on phosphatidylinositol 3'-kinase (PI3K) activity.

PSA is synthesized from sialic acid building blocks by the sialyltransferases STX and PST. In Molecular and Cellular Biology, Angata et al. examined STX^-/-/PST^-/- mice and also uncovered a role for PSA in enhancing the directed migration of neuronal and glial precursors. Most STX^-/-/PST^-/- double knockout mice died shortly after birth. They showed gross anatomical brain defects such as a pronounced thickening of the rostral migratory stream, a migration pathway of neuronal precursors from the SVZ. Comparison of embryonic and neonatal brain tissues confirmed that glial and neuronal precursor cell migration from the SVZ was strongly reduced in brains of mice that lack STX and PST, and hence PSA. Moreover, the number of apoptotic cells in the SVZ and the cortex in the few surviving double knockout mice was higher than in control mice.

Interestingly, the expression of Pax6, a transcription factor required for cell migration, was decreased in the PSA-deficient mice. This finding suggests that PSA can regulate protein expression pathways in addition to its role in modulating cell adhesion and mobility. Finally, glial precursor cells from STX/PST-deficient mice differentiated into glial cells earlier than precursors from normal mice, suggesting that PSA also retards cell differentiation.

In sum, the results of these studies provide critical building blocks for the future development of therapeutic strategies that rely on the guided migration of endogenous and transplanted precursor cells for neural repair.

Author: Mirko von Elstermann