Abstract
Brain injuries such as trauma and stroke lead to glial scar formation by reactive astrocytes which produce and secret axonal outgrowth inhibitors. Chondroitin sulfate proteoglycans (CSPG) constitute a well-known class of extracellular matrix molecules produced at the glial scar and cause growth cone collapse. The CSPG glycosaminoglycan side chains composed of chondroitin sulfate (CS) are responsible for its inhibitory activity on neurite outgrowth and are dependent on RhoA activation. Here, we hypothesize that CSPG also impairs neural stem cell migration inhibiting their penetration into an injury site. We show that DCX+ neuroblasts do not penetrate a CSPG-rich injured area probably due to Nogo receptor activation and RhoA/ROCK signaling pathway as we demonstrate in vitro with neural stem cells cultured as neurospheres and pull-down for RhoA. Furthermore, CS-impaired cell migration in vitro induced the formation of large mature adhesions and altered cell protrusion dynamics. ROCK inhibition restored migration in vitro as well as decreased adhesion size.
Highlights
In the adult mammalian brain, neuroblasts from the subventricular zone (SVZ) travel through the rostral migratory stream towards the olfactory bulb, where they differentiate and integrate into the local circuitry [1,2,3]
Interaction of neural stem cells (NSC) with extracellular matrix (ECM) components is critical for migration, and external stimuli are transduced into cytoskeletal rearrangements that influence neuroblast migration by the action of RhoGTPases [6]
Migratory DCX+ neuroblasts leave the SVZ niche located at the lateral ventricle wall and migrate towards the injury guided by chemokines, ECM components, and blood vessels [5, 29, 30]
Summary
In the adult mammalian brain, neuroblasts from the subventricular zone (SVZ) travel through the rostral migratory stream towards the olfactory bulb, where they differentiate and integrate into the local circuitry [1,2,3]. Glial scars are produced mainly by reactive astrocytes, oligodendrocytes, and microglia. These cells produce axonal growth inhibitory molecules, such as chondroitin sulfate proteoglycans (CSPG), Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMGp) [8]. CSPG comprise a heterogeneous class of proteoglycans that includes, in the brain, RPTPβ, phosphacan, NG2, brevican, aggrecan, and neurocan. These membrane and ECM proteoglycans play important roles during CNS development, including control of axonal outgrowth and guidance [9, 10], directing neuronal precursor migration and regulating Purkinje cell differentiation and maturation in the developing
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