EphrinB3 restricts endogenous neural stem cell migration after traumatic brain injury

Abstract

Traumatic brain injury (TBI) leads to a series of pathological events that can have profound influences on motor, sensory and cognitive functions. Conversely, TBI can also stimulate neural stem/progenitor cell proliferation leading to increased numbers of neuroblasts migrating outside their restrictive neurogenic zone to areas of damage in support of tissue integrity. Unfortunately, the factors that regulate migration are poorly understood. Here, we examine whether ephrinB3 functions to restrict neuroblasts from migrating outside the subventricular zone (SVZ) and rostral migratory stream (RMS).We have previously shown that ephrinB3 is expressed in tissues surrounding these regions, including the overlying corpus callosum (CC), and is reduced after controlled cortical impact (CCI) injury. Our current study takes advantage of ephrinB3 knockout mice to examine the influences of ephrinB3 on neuroblast migration into CC and cortex tissues after CCI injury. Both injury and/or ephrinB3 deficiency led to increased neuroblast numbers and enhanced migration outside the SVZ/RMS zones. Application of soluble ephrinB3-Fc molecules reduced neuroblast migration into the CC after injury and limited neuroblast chain migration in cultured SVZ explants. Our findings suggest that ephrinB3 expression in tissues surrounding neurogenic regions functions to restrict neuroblast migration outside the RMS by limiting chain migration.

EphB3 interacts with initiator caspases and FHL-2 to activate dependence receptor cell death in oligodendrocytes after brain injury

“…It is likely that EphB3-mediated OL cell death plays a major role in the observed functional deficits associated with CCI injury; however, we cannot rule out the possibility that multiple cell types may contribute to the improved behavioural functions associated with EphB3 deletion or ephrinB3 administration. In particular, improved survival of neural progenitor cells and endothelial cells may stabilize the blood–brain barrier and injury microenvironment ( Dixon et al , 2016 ; Assis-Nascimento et al , 2018 ). We have also shown that EphB3 signalling may have deleterious effects on synaptic stability after TBI, suggesting that decreased EphB3 activity may reduce the global dysfunction of networks in the injured brain ( Perez et al , 2016 ).…”

Selective inhibition of soluble TNF using XPro1595 relieves pain and attenuates cerulein-induced pathology in mice

“…To assess the extent of circulating macrophage infiltration within the pancreas, the immunohistochemistry images were quantitated for the level of IBA-1 expression [ 39 , 40 ]. Images were imported into ImageJ software (NIH), converted to gray scale, thresholded, and the area fraction of pixels positive for IBA-1 was quantitated, the values for each photograph were averaged per section, per animal, and then per group [ 41 , 42 ]. The same protocol was applied to brain sections containing hippocampus at 7 days post-induction to quantitate astrocyte reactivity using the GFAP antibody.…”

Explant Methodology for Analyzing Neuroblast Migration

“…In rodents, the SVZ is a thin ‘wedge’ of cells, covering the entire wall of the lateral ventricle (Mirzadeh et al ., 2010; Paez-Gonzalez et al ., 2014; Dixon et al ., 2016). Within the SVZ the slow-dividing astrocyte-like type B cells differentiate into rapidly dividing type C neural progenitor cells (also known as transit amplifying cells) that give rise to double-cortin-positive type A neuroblasts, although oligodendrocytes and astrocytes are also capable of being produced (Garcia-Verdugo et al ., 1998; Tavazoie et al ., 2008; Rikani et al ., 2013).…”

“…Ablation studies suggest it takes approximately 2 days for fast dividing type C neural progenitor cells to populate the SVZ, and an additional 2.5 days for neuroblasts to appear (Doetsch et al ., 1999). A small percentage of these neuroblasts are capable of migrating ectopically out of the RMS into surrounding tissues in naïve mice; however, this phenomenon is drastically increased following brain injury (Dixon et al ., 2016). The ability of neuroblasts to redirect their migratory routes towards damaged tissues has been shown to have beneficial effects on brain recovery (Li et al ., 2010; Dixon et al ., 2015), which can occur as early as 3 days post-injury (Ramaswamy et al ., 2005; Dixon et al ., 2016).…”

“…Unfortunately, these conditions limit the ability to analyze factors that regulate type A neuroblasts, a transient stage between the stem cell and neuron. To counteract this limitation; pieces of SVZ-derived tissue can be harvested and cultured as explants in a Matrigel containing laminin and collagen, which maintains the neural stem cells in their neuroblast state, allowing them to migrate (Ward and Rao, 2005; Dixon et al ., 2016). Furthermore, neuroblast migration from cultured SVZ explants has similar characteristics to those observed in the RMS.…”