Endocrine Abstracts

Constitutive neurogenesis in the adult mammalian brain (sub-ventricular zone, SVZ and dentate gyrus) implies the capacity for self-repair following brain injury. However, brain injury is usually permanently debilitating as neuronal self-repair responses are not sustained and resident neural stem cells (NSC) do not repopulate damaged tissue. Identification of NSC differentiating factors transiently activated post-injury will be key to enhancing NSC mobilisation and differentiation in the lesioned brain. We hypothesise that limited activation of resident NSC occurs in lesioned brain, with some initiation of migration to lesion sites in an abortive attempt to repopulate degenerating neurons. Adult C57BL6 mice sustained a penetrating lesion of the right hemisphere into the brain cortex and lateral ventricle. Tissue was processed for immunohistochemistry revealing proliferating cells (PCNA), NSC (nestin, CD133, c-kit), and differentiating neurons (doublecortin, PSA-NCAM). Proliferating cells were identified in the injured SVZ and lesion site. CD133 and c-kit immuno-positive NSC were observed at the lesion 3–6 days post-injury and nestin in the SVZ after day 6. Enhanced numbers of doublecortin- and PSA-NCAM-positive neurons were apparent in the SVZ at 10 days. These observations suggest injury-induced NSC activation and progression towards an immature neuronal phenotype. The wound microenvironment also exhibited increased FGF-2 expression, known to stimulate neuronal differentiation from NSC. Together these signals may represent re-expression of developmental cues. We have shown that mouse embryos exhibit Dcx expression from E10 and PSA-NCAM from E18 in differentiating NSC of the outer brain cortex. Identification of neural differentiation signals during development and after brain injury suggests a potential strategy to build adult NSC capacity, by potentiating the passage of endogenous or exogenous NSC down a neuronal lineage. Complementation of endogenous NSC activation with exogenous stem cells with capacity to commit to a neuronal lineage may supplement naturally occurring neurogenesis, thereby enhancing functional recovery after brain injury.