Neural stem cells
Ekaterina Gracheva, "Elements"
This photo shows a mouse neuron (purple) against the background of its predecessors – neural stem cells (see Neural stem cell). Yellow indicates the nuclei of cells, blue indicates the cytoskeleton. Photo © Nadia Efimova from the website nikonsmallworld.com . The micrograph was obtained using a confocal microscope, magnification 40×. The picture was included in the Images of Distinction category of the prestigious Nikon Small World 2020 international micrography competition.
All neurons of the central nervous system, as well as astroglia and oligodendroglia cells, are formed from neural stem cells (NSCs). NSCs are most active during embryonic development, when the nervous system is formed. The neural plate and then the neural tube consist of a single layer of neuroepithelium (see Neuroepithelial cell). These cells are primary neural stem cells. They divide symmetrically: one division leads to the formation of two identical cells. This is the first quality of stem cells – self-renewal. Such division is necessary to develop a pool of cells from which the nervous system will develop.
Later, the cells change their division style to asymmetric. When dividing, one neuroepithelial cell and one radial glial cell are obtained from one neuroepithelial cell. This respects another property of stem cells – the ability to give different cells. Radial glial cells also belong to neural stem cells. They are the source of neurons that will never share, astroglia cells and intermediate neural progenitor cells that can share once or twice more to turn into neurons or glia cells. In addition, radial glial cells work as guides, helping neurons to be distributed in the growing central nervous system.
The formation of neurons in the mouse brain. Neuroepithelial cells are activated on the 8th day of embryonic development (E8). On the 14th day (E14), they turn into early radial glial cells. Radial glial cells can either transform into neurons (neuron) directly, or differentiate into intermediate neural progenitor cells (nIPCs), from which neurons are formed. During development, radial glial cells can also form intermediate progenitor cells of oligodendrocytes (oIPCs) and astrocytes (aIPCs), which differentiate and become part of the nervous system. Figure from the article by B. Yao and P. Jin, 2014. Unlocking epigenetic codes in neurogenesis.
By the time of birth, almost all neurons are present in the mammalian brain, and there is practically no radial glia left. With some exceptions.
In the late XIX – early XX century, the great histologist Santiago Ramon y Cajal wrote: "After the completion of development, the source of growth and regeneration of axons and dendrites dries up irrevocably. In adult centers, neural pathways can somehow get better, end and remain unchanged. Everything can perish, nothing can be restored. The science of the future is destined to change this heavy sentence, if it is possible." Science has changed.
Back in the 1960s, Joseph Altman and Gopal Das showed that new neurons are formed in the brains of young rats. A similar process was observed in canaries. The source of these neurons was found later. In most mammals, after birth, new neurons are formed in two parts of the brain: on the walls of the lateral ventricles of the brain (subventricular zone) and in the dentate gyrus of the hippocampus (in the subgranular zone). In these places, neural stem cells remain (which are very similar to embryonic radial glia), which give new neurons and glia cells.
Neurons from the subventricular zone migrate to the olfactory bulb. Without them, it would be difficult for animals to subtly distinguish smells and associate smells with a reward. Neurons formed in the subgranular zone are involved in the work of the dentate gyrus. They are important for memory formation, learning, and possibly play a functional role in stress and depression. Are new neurons being formed in the adult brain? Probably, yes, but so far scientists cannot agree on the contribution of new neurons to nervous activity.
But how to replenish nerve cells that for some reason were lost in other parts of the central nervous system? The idea to transplant NSCs for the treatment of neurodegenerative diseases arose in the early 2000s. Thus, NSC was administered to rats – models of amyotrophic lateral sclerosis (ALS). Scientists have shown that cells can differentiate into neurons and glia and prolong the life of experimental animals. Such studies have become the main clinical research, where patients with ALS have already been injected with NSCs into the spinal cord. This led to a slight improvement in the condition of patients. Clinical studies were also conducted on the introduction of NSC in patients with spinal cord injury, where modest but positive results were observed.
Unfortunately, in such studies, an important question is added to the standard questions of cell therapy, such as whether stem cells will turn into the right tissues: where do neural stem cells come from?
Various cell lines of neural stem cells are available to scientists. Mice NSCs are obtained from the embryonic brain or from the subventricular and subgranular zones of the adult brain. There are also human NSC lines that are obtained from abortive material. Such lines were used in the clinical studies mentioned above. But receiving such lines is not allowed everywhere and is associated with ethical issues. In addition, these are cells of other organisms, not the patient himself, and they can cause an undesirable response of the body to such an invasion. Therefore, research in this direction now often begins with the use of embryonic stem cells and induced pluripotent stem cells. Neural stem cells can be obtained from them and used not only in clinical, but also in fundamental research. For example, using this approach, miniature models of the embryonic brain have been obtained, which can be used to study the development of the human nervous system and some of its diseases in real time. And recently, similar models have shown that SARS-CoV-2 is apparently capable of infecting neurons in the brain. In addition, NSCs can be useful when searching for new drugs.
There are three different methods for obtaining neural stem cells. The first (on the left) – isolation from the tissues of the central nervous system (from the embryonic and adult brain or spinal cord tissues). Second (in the center) – production from pluripotent cells (embryonic stem cells or induced pluripotent stem cells). The third method is transdifferentiation from somatic cells (skin fibroblasts, epithelial cells isolated from urine or blood cells). These cells are easy to obtain in a clinic setting. Neural stem cells obtained by these methods can be immortalized (see Immortalized cell line) using genetic engineering methods. Figure from the article Y. Tang et al., 2017. Current progress in the derivation and therapeutic application of neural stem cells.
We are still a long way from growing a full-sized brain, and from affordable treatment with neural stem cells. But the dogma of Ramon y Cajal has been broken, which means that one of the main barriers on this path has already been overcome.
Portal "Eternal youth" http://vechnayamolodost.ru