For over 100 years, the adult mammalian brain was thought to remain structurally constant after birth, with no further addition of neurons. This central dogma stemmed from the histological and anatomic studies of Koelliker, His, and Cajal. In his seminal work, Cajal commented “Once the development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. In the adult centers, the nerve paths are something fixed, ended, and immutable. Everything may die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree.” Up to the mid1980s, autoradiographic analysis of S-phase nuclei suggested that neurogenesis was limited to prenatal and early postnatal stages. Several developments eventually led to the general acceptance of adult-generated neurons. In vivo fatemapping using BrdU (5-bromo-3'-deoxyuridine) revealed that neurons constitute a large proportion of adult-born cells. The trophic and mitogenic actions of growth factors, including fibroblast growth factors (FGF) and epidermal growth factor (EGF) family proteins, further permitted the long-term maintenance and subsequent study of neural cells in vitro.
In the early 1990s, neural stem cells were isolated from the adult brain that exhibited colony-forming activity, self-renewal, and multipotency. These bona fide neural stem cells (NSCs) were also identified in other regions of the mammalian nervous system. Advances in the derivation and culture of NSCs led to the idea that these cells could be used to restore normal function in the diseased or damaged brain. Numerous transplantation experiments have been undertaken to test the therapeutic potential of NSCs. The beneficial effects of transplanted NSCs were first demonstrated in a mouse model of lysosomal storage disease. Upon neonatal injection, clonally-derived progenitors exhibited widespread engraftment and ameliorated neuropathological lesions. Different sources of NSCs have since been identified for therapeutic use, which are elaborated upon in this section.
Creative Biomart provides kinds of neural stem cell markers to study these cells for therapeutic use.
Identification of NSCs in the embryonic VZ
Multipotent NSCs reside in the germinal neuroepithelium or ventricular zone (VZ) of the embryonic brain. Early in development, neuroepithelial cells in the VZ undergo expansion through symmetric division. At the onset of cortical neurogenesis, they elongate and convert into radial glial (RG) cells. RG cells divide asymmetrically to generate neurons directly or indirectly through intermediate progenitors cells (IPCs). Newly generated neurons migrate along radial glial fibers past earlier-generated cells to reside in successively more superficial positions. Postmitotic progeny ultimately coalesce into six distinct cortical layers that have specific projections patterns. Sister excitatory neurons are also radially aligned in ontogenic columns. Subsequent studies have demonstrated that clonally related neurons within a column electrically couple and preferentially form synaptic connections.
The fate of germinal cells in the developing cortex is temporally regulated. Heterochronic transplantation studies have examined the laminar fate of early and late cortical progenitor cells. Early cortical progenitors, which give rise to deep layer neurons, can retain this fate even after being transplanted into an older host. Late cortical progenitors grafted into the cerebral cortex of a younger host environment do not acquire an earlier fate. Instead, these cells are restricted to producing upper layer neurons. Even in culture, individual progenitor cells sequentially generate distinct neuronal subtypes in the same order as they occur in vivo, suggesting that this phenomenon is cell-autonomous. The separate timing of neurogenesis and gliogenesis in the developing cortex is also well established. Isolated multipotent NSCs in vitro recapitulates the normal order of cell generation: neurons followed by glia. Gliogenic cues, transcription factor sequences, DNA methylation changes, and chromatin modifications may underlie this switch from neurons to glia.