Comparison of Cortical and White Matter Traumatic Brain Injury Models Reveals Differential Effects in the Subventricular Zone and Divergent Sonic Hedgehog Signaling Pathways in Neuroblasts and Oligodendrocyte Progenitors

Abstract

The regenerative capacity of the central nervous system must be optimized to promote repair following traumatic brain injury (TBI) and may differ with the site and form of damage. Sonic hedgehog (Shh) maintains neural stem cells and promotes oligodendrogenesis. We examined whether Shh signaling contributes to neuroblast (doublecortin) or oligodendrocyte progenitor (neural/glial antigen 2 [NG2]) responses in two distinct TBI models. Shh-responsive cells were heritably labeled in vivo using Gli1-CreERT2;R26-YFP bitransgenic mice with tamoxifen administration on Days 2 and 3 post-TBI. Injury to the cerebral cortex was produced with mild controlled cortical impact. Yellow fluorescent protein (YFP) cells decreased in cortical lesions. Total YFP cells increased in the subventricular zone (SVZ), indicating Shh pathway activation in SVZ cells, including doublecortin-labeled neuroblasts. The alternate TBI model produced traumatic axonal injury in the corpus callosum. YFP cells decreased within the SVZ and were rarely double labeled as NG2 progenitors. NG2 progenitors increased in the cortex, with a similar pattern in the corpus callosum. To further test the potential of NG2 progenitors to respond through Shh signaling, Smoothened agonist was microinjected into the corpus callosum to activate Shh signaling. YFP cells and NG2 progenitors increased in the SVZ but were not double labeled. This result indicates that either direct Smoothened activation in NG2 progenitors does not signal through Gli1 or that Smoothened agonist acts indirectly to increase NG2 progenitors. Therefore, in all conditions, neuroblasts exhibited differential Shh pathway utilization compared with oligodendrocyte progenitors. Notably, cortical versus white matter damage from TBI produced opposite responses of Shh-activated cells within the SVZ.

Generation of reactive astrocytes from NG2 cells is regulated by sonic hedgehog

“…It has been shown that Shh signaling influences proliferation of several cell types following injuries (Cheng et al, ; He et al, ; Sims et al, ); however, we did not find any impact of this signaling pathway on the proliferation of Tomato+ NG2 cells after FCI. These results correspond with previously shown importance of Shh signaling in the proliferation of many cell types except Olig2‐positive NG2 cells after injury (Mierzwa et al, ; Pitter et al, ). Several studies demonstrated that Shh increases the number of proliferating astrocytes after CNS pathologies (Amankulor et al, ; Sirko et al, ); nevertheless, this phenomenon could also be explained by an increased number of astrocytes per mm 2 , which are derived from NG2 cells due to the activation of Shh signaling pathway.…”

Introductory Chapter: Introduction to Update in Amyotrophic Lateral Sclerosis and Review of this Condition in Sportsmen

“…Other authors supported this hypothesis as well [42][43][44][45][46] and we considerate that those results cannot be transferred to human beings.…”

Repetitive Model of Mild Traumatic Brain Injury Produces Cortical Abnormalities Detectable by Magnetic Resonance Diffusion Imaging, Histopathology, and Behavior

“…46–48 Our previous studies in the s-mTBI model found that NG2 cell density increased in the corpus callosum and cortex during the initial weeks post-injury with less of an elevation by 6 weeks post-injury. 20,49 In r-mTBI mice, the NG2 cell population was not affected in the corpus callosum or cortex in the post-imaging 6-week cohort (Fig. 6C,D,F,H).…”