Temporal Patterns of Cortical Proliferation of Glial Cell Populations after Traumatic Brain Injury in Mice

Abstract

TBI (traumatic brain injury) triggers an inflammatory cascade, gliosis and cell proliferation following cell death in the pericontusional area and surrounding the site of injury. In order to better understand the proliferative response following CCI (controlled cortical impact) injury, we systematically analyzed the phenotype of dividing cells at several time points post-lesion. C57BL/6 mice were subjected to mild to moderate CCI over the left sensory motor cortex. At different time points following injury, mice were injected with BrdU (bromodeoxyuridine) four times at 3-h intervals and then killed. The greatest number of proliferating cells in the pericontusional region was detected at 3 dpi (days post-injury). At 1 dpi, NG2+ cells were the most proliferative population, and at 3 and 7 dpi the Iba-1+ microglial cells were proliferating more. A smaller, but significant number of GFAP+ (glial fibrillary acidic protein) astrocytes proliferated at all three time points. Interestingly, at 3 dpi we found a small number of proliferating neuroblasts [DCX+ (doublecortin)] in the injured cortex. To determine the cell fate of proliferative cells, mice were injected four times with BrdU at 3 dpi and killed at 28 dpi. Approximately 70% of proliferative cells observed at 28 dpi were GFAP+ astrocytes. In conclusion, our data suggest that the specific glial cell types respond differentially to injury, suggesting that each cell type responds to a specific pattern of growth factor stimulation at each time point after injury.

A single dose of PPARγ agonist pioglitazone reduces cortical oxidative damage and microglial reaction following lateral fluid percussion brain injury in rats

“…In our study, GFAP was used as a specific marker of reactive astrocytosis (Eng et al, 2000), and a statistically significant increase in its expression was shown in the injured rat cortex following LFPI. This is in agreement with previously published findings obtained in the same (Di Giovanni et al, 2005;Okimura et al, 1996), and also in the other TBI models (Liu et al, 2014;Nonaka et al, 1999;Susarla et al, 2014). Results of the present study also revealed that pioglitazone used in our experimental conditions did not significantly change the level of reactive astrocytosis in the injured animals.…”

Strategies for CNS repair following TBI

“…This process begins with an expansion of the NG2+ cell population that is contributory to the forming glial scar. A predominantly microglial cell proliferation then appears to follow (Susarla et al, 2014). This sequence of cell proliferation and cell invasion to form the glial scar is also termed reactive gliosis.…”

Surgical injury-induced early neocortical microvascular changes and characteristics of the cells populating the peri-lesion zone

“…This observation may help explaining the low number of cells with immature neuron phenotype reported in the peri-injury zone, both in our and in other models of traumatic brain injury (Susarla et al 2014).…”

“…However, nestin re-expression can also take place in situ (in resident cells) in the adult brain damaged region during formation of the glial scar (Michalczyk and Ziman 2005). Notably, the emergence of a small number of DCX-positive cells in the neocortex after its injury was reported in a mouse model (Susarla et al 2014). Yet another source of these cells may be NG2-positive mesenchymal stem cells that have neural lineage potential (Okolicsanyi et al 2014).…”

“…Yet another source of these cells may be NG2-positive mesenchymal stem cells that have neural lineage potential (Okolicsanyi et al 2014). It was shown that NG2-positive cells proliferate quickly after brain injury (Susarla et al 2014) and can differentiate into oligodendrocytes that take part in reconstruction of the brain parenchyma (Nishiyama et al 2009). Many, while not all, researchers indicated also to the potential of these cells for differentiation into both astroglia, synantocytes and neurons depending on the type and extent of the injury, and on the state of its surroundings (Butt et al 2005, Aguirre et al 2007, Zhu et al 2008, Haselkorn et al 2010, Morrens et al 2012).…”