Neurogenesis and brain injury: managing a renewable resource for repair

Abstract

The brain shows limited ability to repair itself, but neurogenesis in certain areas of the adult brain suggests that neural stem cells may be used for structural brain repair. It will be necessary to understand how neurogenesis in the adult brain is regulated to develop strategies that harness neural stem cells for therapeutic use.

Figure 1

Germinal centers in the adult brain. Neurogenesis in the adult brain is largely confined to two germinal centers: the dentate gyrus and the subventricular zone, shown schematically (a) and in a corresponding sagittal section of the rodent brain (b). Insets in b show the position of high-resolution micrographs in c–f. In the dentate gyrus (c), newly generated cells are detected through incorporation of the thymidine analog BrdU and labeled with a green fluorophore (Cy2). These cells differentiate into mature neurons, as seen by their coexpression of the marker NeuN (red) but not S100β (blue), a marker for mature astrocytes. In contrast, cells generated in the subventricular zone (d) do not differentiate into mature neurons (red) but migrate away through the rostral migratory stream (RMS). Within the RMS (e), newly generated cells are surrounded by astrocytes (glial fibrillary acidic protein [GFAP], blue) and begin to express immature neuronal markers (polysialylated neural cell adhesion molecule [PSA-NCAM], red) as they migrate to the olfactory bulb. Upon arrival in the olfactory bulb (f), newly generated cells differentiate into mature neurons (NeuN, red), but not astrocytes (S100β, blue).

Figure 2

Therapeutic strategies for brain repair by stem cells. For brain repair in regions outside of the germinal centers, such as the cerebral cortex, stem cells may contribute to repair through recruitment or replacement. In the case of recruitment (a), the environment in the non-neurogenic region must be enhanced with appropriate environmental signals to attract endogenous neural stem cells, possibly from the germinal centers, to expand this population of cells, and to instruct their differentiation into appropriate neurons. This environmental enhancement could most likely be achieved using in vivo gene therapy leading to transgene expression by endogenous cells and may require a precise temporal and spatial delivery of appropriate transgenes to achieve the desired outcome. In the case of replacement (b), neural stem cells derived from embryonic, fetal, or adult sources could be expanded in vitro, directed down specific neuronal lineages, and genetically modified to express the necessary environmental signals. Thus committed to the correct phenotype and expressing necessary environmental signals to ensure their survival, these cells could then be grafted to the target region. Alternatively (c), the environment could be enhanced by gene delivery before (or possibly after) the grafting of the replacement neural stem cells.

Figure 3

Endogenous cortical proliferation is enhanced following FGF-2 gene delivery. (a) Endogenous proliferation occurs infrequently in the naive entorhinal cortex. Newly generated cells labeled by BrdU administration over 48 hours are indicated by the arrow and shown at higher magnification in the inset. (b) Intracerebral saline injection prior to BrdU treatment produced no visible increase in proliferation in the entorhinal cortex. (c) Injection of adenovirus expressing the reporter gene LacZ produced little effect on proliferation in the entorhinal cortex. (d) Adenovirus-mediated gene delivery of FGF-2 produced a substantially increased proliferation in the entorhinal cortex.