Activation of endogenous neural stem cells after traumatic brain injury

Abstract

BackgroundInterest in promoting regeneration of the injured nervous system has recently turned to the use of endogenous stem cells. Elucidating cues implicated in driving these precursor cells out of quiescence after injury and the signals that drive them towards neuronal and glial fates will help harness these cells for repair. In the cortex, cells expressing the astrocytic marker, glial acidic fibrillary protein (GFAP), generate both neurons and glia, but only after a stab injury to the cortex. This observation raises the possibility that a source of potential endogenous stem cells resides in the cortex. We have focused on the mechanisms that underly this injury induced activation in traumatic brain injury. MethodsUsing a biomechanically validated in-vitro organotypic stretch injury model, we cultured cortico-hippocampal slices from postnatal mice. A stretch injury, equivalent to a severe traumatic brain injury, was applied to the slices and the neurogenic potential of the tissue in both the cortex and the hippocampus was measured. FindingsIn uninjured cortex, proliferative potential under in-vitro conditions was virtually absent in older slices (equivalent postnatal day 15 vs 8). However, after a severe stretch injury, this potential was restored in injured outer cortex. Using slices from mice expressing a fluorescent reporter on the human GFAP promoter, we showed that GFAP-positive cells accounted for the majority of the proliferating neurospheres formed, and that these cells were likely to arise from the cortical parenchyma and not the subventricular zone. Upregulation of Sonic Hedgehog signalling, a pathway known to regulate stem-cell proliferation, correlated with restoration of regenerative potential after traumatic brain injury. We found an increase in mRNA expression of transforming growth factor β, a cytokine known to increase the number of GFAP-expressing cells in the cortex. InterpretationOur results indicate that a source of quiescent endogenous stem cells residing in the cortex proliferate in-vitro after traumatic brain injury. Moreover, these proliferating cells are multipotent and are derived mostly from GFAP-expressing cells. We are investigating the contribution of signalling pathways to this stem-cell activation. Our findings raise the possibility of using this endogenous source of stem cells for repair after traumatic brain injury. FundingThe Royal College of Surgeons of England, Wessex Medical Research, Academy of Medical Sciences.