Neural stem cells

Neural stem cells (NSCs) are the self-renewing, multipotent cells that generate the main phenotypes of the nervous system. In 1989, Sally Temple described multipotent, self-renewing progenitor and stem cells in the subventricular zone of the mouse brain (Temple, S, Nature, 1989). In 1992, Brent A. Reynolds and Samuel Weiss were the first to isolate neural progenitor and stem cells from the adult striatal tissue, including the subventricular zone — one of the neurogenic areas — of adult mice brain tissue. In the same year the team of Constance Cepko and Evan Y. Snyder were the first to isolate multipotent cells from the mouse cerebellum and stable transfected them with the oncogene v-myc. Interestingly this molecule is one of the genes widely used now to reprogrammed adult non-stem cells into pluripotent stem cells. Since then, neural progenitor and stem cells have been isolated from various areas of the adult brain, including non-neurogenic areas, such as the spinal cord, and from various species including human.

Functions
Epidermal growth factor (EGF) and fibroblast growth factor (FGF) are mitogens that promote neural progenitor and stem cell growth in vitro, though other factors synthesized by the neural progenitor and stem cell populations are also required for optimal growth. It is hypothesized that neurogenesis in the adult brain originates from NSCs. The origin and identity of NSCs in the adult brain remain to be defined.

Function of Neural stem cells (NSC) during disease
NSCs have an important role during development producing the enormous diversity of neurons, astrocytes and oligodendrocytes in the developing CNS. They also have important role in adult animals, for instance in learning and hippocampal plasticity in the adult mice in addition to supplying neurons to the olfactory bulb in mice.

Notably the role of NSCs during diseases is now being elucidated by several research groups around the world. The responses during stroke, multiple sclerosis, parkinson's disease in humans and in model of these diseases is part of the current investigation. The results of this ongoing investigation may have future applications to treat human neurological diseases.

Neural stem cells have been shown to engage in migration and replacement of dying neurons in classical experiments performed by Sanjay Magavi and Jeffrey Macklis. Using a laser-induced damage of cortical layers, Magavi showed that SVZ neural progenitors expressing Doublecortin, a critical molecule for migration of neuroblasts, migrated long distances to the area of damage and differentiated into mature neurons expressing NeuN, a widely used neuronal marker. In addition Masato Nakafuku's group from Japan showed for the first time the role of hippocampal stem cells during stroke in mice. These results demonstrated that NSCs can engage in the adult brain as a results of injury. Furthermore, In 2004 based on early work of Evan Synder's group, that showed that NSCs migrate to brain tumors in a directed fashion, Jaime Imitola, M.D and colleagues from Harvard demonstrated for the first time, a molecular mechanism for the responses of NSCs to injury, they showed that chemokines released during injury such as SDF-1a were responsible for the directed migration of human and mouse NSCs to areas of injury in mice. Since then other molecules have been found to participate in the responses of NSCs to Injury. All these results have been widely reproduced and expanded by other investigators joining the classical work of Altman and Sidman in 1960's as evidence of the responses of adult NSCs activities and neurogenesis during homeostasis and injury. The search for additional mechanisms that operate in the injury environment and how they influence the responses of NSCs during acute and chronic disease is matter of intense research.

Assay
Neural stem cells are routinely studied in vitro using a method referred to as the Neurosphere Assay (or Neurosphere culture system), first developed by Reynolds and Weiss. Neurospheres are intrinsically heterogeneous cellular entities almost entirely formed by a small fraction (1 to 5%) of slowly dividing neural stem cells and by their progeny, a population of fast-dividing nestin-positive progenitor cells. The total number of these progenitors determines the size of a neurosphere and, as a result, disparities in sphere size within different neurosphere populations may reflect alterations in the proliferation, survival and/or differentiation status of their neural progenitors. Indeed, Leone et al. (2005) have reported that loss of β1-integrin in a neurosphere culture  does not significantly affect the capacity of β1-integrin deficient stem cells to form new neurospheres, but it influences the size of the neurosphere:  β1-integrin deficient neurospheres were overall smaller due to increased cell death and reduced proliferation.

While the Neurosphere Assay has been the method of choice for isolation, expansion and even the enumeration of neural stem and progenitor cells, several recent publications have highlighted some of the limitations of the neurosphere culture system as a method for determining neural stem cell frequencies. In collaboration with Reynolds, STEMCELL Technologies has developed a collagen-based assay, called the Neural Colony-Forming Cell (NCFC) Assay, for the quantification of neural stem cells. Importantly, this assay allows discrimination between neural stem and progenitor cells.

Neural Stem Cell Institutes
The damaged central nervous system (CNS) tissue has very limited regenerative and repair capacity so that loss of neurological function is often chronic and progressive. Cell replacement from stem cells is being actively pursued as a therapeutic option. Recently in 2009, a research institute dedicated solely to translating neural stem research into therapies for patients was created outside of Albany, NY, The Neural Stem Cell Institute.