Neural stem cells: historical perspective and future prospects

Abstract

How a single fertilized cell generates diverse neuronal populations has been a fundamental biological problem since the 19(th) century. Classical histological methods revealed that postmitotic neurons are produced in a precise temporal and spatial order from germinal cells lining the cerebral ventricles. In the 20(th) century, DNA labeling and histo- and immunohistochemistry helped to distinguish the subtypes of dividing cells and delineate their locations in the ventricular and subventricular zones. Recently, genetic and cell biological methods have provided insights into sequential gene expression and molecular and cellular interactions that generate heterogeneous populations of NSCs leading to specific neuronal classes. This precisely regulated developmental process does not tolerate significant in vivo deviation, making replacement of adult neurons by NSCs during pathology a colossal challenge. In contrast, utilizing the trophic factors emanating from the NSC or their derivatives to slow down deterioration or prevent death of degenerating neurons may be a more feasible strategy.

Figure 1. A Potpourri of Classical Depiction of Neural Glial Stem Cells

A. Illustration taken from the work of Wilhelm His (1904) on the human embryonic forebrain. Notice the incredible detail and fidelity with which cell types [mitotic figures, “pongiobasts” (radial glia) migrating neurons, etc.] were depicted without the use of modern methods, including the horizontal and vertical (asymmetric)_division of the mitotic cells. B. The drawings of the “enedymal glial cells” in the human fetal cerebrum at 10 week old stand with Golgi method (Retzius, 1893b). C. Epithelial (radial glial) and neuroglial cells of the cerebral cortex at later stage of development in the neonatal rabbit stained with the Golgi method depicted by Ramón y Cajal (Ramon y Cajal, 1909). D. Primordial epithelium including trnsition to glial cells morphology in the spinal cord of the chick embryo-3rd day of incubation when, according to Ramón y Cajal, they become stainable by the Golgi method. E. Characteristic lamellate expansion on the radial shafts of epithelial (radial glial) cells. See the text for further explanation.

Figure 2. A Modern Depiction of Neural Stem Cells

Schema of the heterogeneity of stem cells in the mammalian forebrain obtianed by modern methods based on evolutionarily most advanced status in human. Initially, neuroepithelial cells constitute the major class of neural stem cells. During the neurogenic phase, these give rise to radial glia (RG) which can self-renew or generate neurons directly or can generate classes of intermediate types such as intermediate neural progenitors (INP) which divide in the SVZ or short neural progenitors (SNP) which contact and divide at the VZ surface—both of which can generate neurons. RG transition into neurogenic SEZ astrocytes and SGZ radial astrocytes during the gliogenic phase. In addition, radial glia can give rise to ependymal (EL) cells, oligodendrocytes (OC) and astrocytes (AC) pre- and peri-natally and in the adjacent dentate gyrus (DG) into prolonged postnatal stage.

Figure 3. Intrinsic Differences in Cell Cycle Length

Representative examples of cultured E60 monkey (A) and stained 16 wg human (C and D) brain slices. Slices were cultured just underneath the media interface in the presence of 25mM BrdU (B). In C, notice the marked separation of the VZ from the SVZ and the band of S-phase cells in the VZ after 1 hour of BrdU application. After 16 hours of BrdU application (D), the VZ had nearly filled with BrdU-labeled nuclei. (E) Data from cumulative BrdU labeling studies on mouse (blue) monkey (black) and human (red) neocortical slice cultures. The slope of the rising phase of the plots = GF/Tc, where GF is growth fraction, or maximum number of proliferating cells in the VZ and Tc is the cell cycle duration. The level of labeling index (LI) saturation (maximum) at later time points defines the GF, or total population of proliferating cells. The time at which the maximum LI is reached is Tc-Ts, or the duration of the cell cycle minus the duration of S-phase. Bar, 100μM.