Endogenous GFAP-Positive Neural Stem/Progenitor Cells in the Postnatal Mouse Cortex Are Activated following Traumatic Brain Injury

Abstract

Interest in promoting regeneration of the injured nervous system has recently turned toward the use of endogenous stem cells. Elucidating cues involved in driving these precursor cells out of quiescence following injury, and the signals that drive them toward neuronal and glial lineages, will help to harness these cells for repair. Using a biomechanically validated in vitro organotypic stretch injury model, cortico-hippocampal slices from postnatal mice were cultured and a stretch injury equivalent to a severe traumatic brain injury (TBI) applied. In uninjured cortex, proliferative potential under in vitro conditions is virtually absent in older slices (equivalent postnatal day 15 compared to 8). However, following a severe stretch injury, this potential is restored in injured outer cortex. Using slices from mice expressing a fluorescent reporter on the human glial fibrillary acidic protein (GFAP) promoter, we show that GFAP+ cells account for the majority of proliferating neurospheres formed, and that these cells are likely to arise from the cortical parenchyma and not from the subventricular zone. Moreover, we provide evidence for a correlation between upregulation of sonic hedgehog signaling, a pathway known to regulate stem cell proliferation, and this restoration of regenerative potential following TBI. Our results indicate that a source of quiescent endogenous stem cells residing in the cortex and subcortical tissue proliferate in vitro following TBI. Moreover, these proliferating cells are multipotent and are derived mostly from GFAP-expressing cells. This raises the possibility of using this endogenous source of stem cells for repair following TBI.

Co-evolution of breast-to-brain metastasis and neural progenitor cells

“…These GFAP+ astrocytes exhibited a hypertrophic morphology comparable to glial scars that form subsequent to traumatic brain injury. Because glial scars are normally associated with neural trauma [25], we asked if the GFAP+ cells that accumulated in and around tumor tissues were also scar-like and contained proliferative astrocytes. We found 20 % of the GFAP+ cell population in the peritumoral brain region co-express the proliferative marker Ki67; with 30 % of these Ki67+/GFAP+ proliferative astrocytes appearing to have infiltrated at the tumor edge (Fig.…”

“…These physiological processes are accentuated near sites of traumatic brain injury, and ischemia, suggesting a role for NPCs and their differentiated descendants in pathological responses. [25, 46]. Thus, although migratory NPCs are known to exist in the post-natal mammalian brain, little is known about any molecular cues mediating their activation, migration, and differentiation in during brain metastasis [47].…”

Cortical Endogenic Neural Regeneration of Adult Rat after Traumatic Brain Injury

“…So many survival head-injured patients were long-term disability for permanent neurological impairment. The economic and health burden of TBI is significant and is predicted to grow further in the next decade [6], [7].…”

Stem cells for therapy in TBI

“…For instance, unlike the formation of the astrocytic glial scar in vivo , isolation of the cells in vitro removed the influence of the injury microenvironment. To demonstrate that the injury-activated cell has the capacity to behave as an NSC outside of the injury milieu, Buffo et al 7 showed that mature astrocytes that had been isolated from the injured cerebral cortex acquired NSC-like properties in vitro through a processed termed ‘dedifferentiation’ and has also demonstrated this using an organotypic model 28. Therefore, while there are cells resident in the cortex as well as cells migrating into the injured cortex that display properties of NSCs, the injury environment prevents them from following a neurogenic fate.…”