Endogenous stem cells to improve the cognitive functions of the damaged brain

Endogenous stem cells for enhancing cognition in the diseased brainAngelique Bordey, translated by Evgenia Ryabtseva

IntroductionAdult neural progenitor cells, or neural stem cells (NST), are preserved in two regions of the adult brain: the subventricular zone and the subgranular zone of the dentate gyrus.

The appearance of new neurons is registered in the subgranular zone of adults and is involved in the functioning of certain types of memory, at least in rodents (Braun and Jessberger, 2014). Neurogenesis occurring in the subventricular zone of the adult brain was initially detected in the olfactory bulb of rodents, and its earlier termination in humans, despite the constant presence of nerve stem cells in this area of the brain, was demonstrated by Sanai et al. (2011). However, the results of a recent study indicate that neurogenesis occurs in the striatum of the subventricular zone of the adult human brain (Ernst et al., 2014). This finding highlights the difference between rodents and humans, as well as the fact that certain regions of the brain demonstrate unexpected opportunities for migration and survival of "newborn" neurons. When considering the possibility of restoring the brain, the most important region is the subventricular zone, since it covers the entire brain, unlike the subgranular zone limited by the hippocampus. Other regions of the brain that also contain NSCs or progenitor cells, such as the hypothalamus, will not be discussed in this article. Before we can talk about functional recovery of the brain, it is necessary to achieve several intermediate goals, an approximate (but not final) list of which is given below.

• Understanding the mechanisms leading to physiological aging and death of NSCs as the body ages. Several mechanisms are involved in various regulatory stages of NSC self-renewal and death. We will pay attention to some of them leading to the age-related death of the NSC. The identification of these mechanisms will provide an opportunity to increase the number of NSCs and guide their differentiation.
• Identification of molecules responsible for determining the direction of differentiation of NSCs and their daughter cells into glial cells or various types of neurons, including intermediate neurons and neurons with long processes.
• Identification of inhibitory molecules that prevent regeneration of brain tissue. Certain signs of recovery have been recorded in the cerebral cortex of rodents, but they are incomplete, probably due to an unfavorable environment.
• And, finally, despite the possibility of carrying out genetic manipulations on rodent NSCs, they cannot be applied to humans. This requires the improvement of delivery systems.

Each of these points is discussed below.

Understanding the mechanisms leading to physiological aging and death of NSCs as the body agesA significant part of the research has been devoted to the study of signaling molecules and mechanisms involved in the regulation of physiological aging of NSCs (Basak and Taylor, 2009), such as signaling mechanisms mediated by Notch and Wnt proteins.

Most of the identified mechanisms are preserved in both embryonic and adult neural stem cells, but individual molecular components may differ. They are also preserved in various niches of the NSC, including in the peripheral parts of the nervous system (Fuchs et al., 2004). Despite the fact that researchers have already identified a wide range of molecules, there are still questions about the exact molecular affiliation of dormant and activated (for example, proliferating) NSCs. There is still no answer to the question of why dormant cells are activated. In other words, which molecules are necessary and sufficient to awaken dormant NSCs? It is also unclear whether the complex of these molecules is identical for all subtypes of NSCs.

In addition, brain damage can have a strong effect on the state of activation of molecular mechanisms in the NSC, as well as on their microenvironment. Very little is known about how NSCs react to damage and how changes in their molecular profile bring them out of a state of rest. The issue is further complicated by the fact that different damages can affect the NSC in different ways. These issues need to be worked out in detail.

Aging is a natural phenomenon that affects NSCs and their microenvironment (van and Franklin, 2013). One of the obvious results of aging is the death of NSCs and, accordingly, a decrease in the possibilities of neurogenesis. The scale and mechanisms of NSC death are different for the subgranular and subventricular zones (Shruster et al., 2010). NSCs of the subgranular zone are terminally differentiated into astrocytes (Encinas et al., 2011). In the subventricular zone, progressive death of intermediate dividing cells occurs with aging (Paliouras et al., 2012). At the molecular level, one of the key roles in the aging process belongs to the mechanism mediated by the mammalian rapamycin target protein complex-1 (mTORC1), which regulates cap-dependent protein translation (Johnson et al., 2013). To date, there is no data on what contribution mTORC1 makes to the aging process of cells in the subgranular zone. In the subventricular zone, mTORC1 is involved in the age-related death of NSCs (Paliouras et al., 2012). In addition, there is an opinion that activation of this mechanism during aging affects the terminal differentiation of NSCs into daughter cells, which contributes to the disappearance of NSCs (Hartman et al., 2013). Therefore, it is necessary to find out whether small doses of the mTORC1 blocker rapamycin can prevent a progressive decrease in the number of NSCs. In other systems of the body, the activity of mTORC1 increases with aging, and there is also evidence of the ability of rapamycin to increase the life expectancy of animal models.

Identification of molecular mechanisms regulating the direction of differentiation for the formation of neurons of various typesAdult NSCs are predominantly differentiated into neurons, especially intermediate neurons.

Scientists have demonstrated that the NSCs of the subventricular zone are genetically determined to transform into certain subtypes of olfactory intermediate neurons (Merkle et al., 2007). The genetic mechanisms that determine this predestination have not yet been identified. In addition, the identification of this molecular program must be carried out at the early stages of development. In other words, the most informative studies will be devoted to the identification of programs that run in embryonic NSCs and determine the fate of these cells in the adult body.

To repair brain damage, in addition to intermediate neurons, it is necessary to form new process neurons. To do this, it is necessary to learn how to reprogram adult NSCs into cells that are close to embryonic NSCs and have a wider range of differentiation possibilities. After the method of creating induced pluripotent stem cells was developed, new reprogramming technologies began to develop very quickly. They need to be tested on adult NSCs in vitro and in vivo.

Identification of inhibitory molecules that prevent regeneration of brain tissueDespite the presence of NSCs in the subventricular zone and nerve progenitor cells in the parenchyma, the adult brain has very limited recovery capabilities.

Perhaps this is a kind of protective mechanism that ensures the preservation of long-term memory. The adult brain tissue contains inhibitory factors (such as NOGO) and there are practically no factors contributing to the survival and integration of NSCs and young neurons, as a result of which a microenvironment unfavorable for neurogenesis is formed. There is a serious need to conduct research on the identification of inhibitory factors in the parenchyma of the brain that prevent the survival and integration of NSCs and immature neurons both under normal conditions and in trauma. In addition, an equally important task is to compare the molecular profiles of different regions of the brain, which are characterized by different levels of recovery capabilities, for example, such as the striatum and cortex (Ernst et al., 2014). Both large-scale molecular screenings and hypothesis-driven approaches can help in solving this issue.

Another limiting factor is access to human brain tissue. Most likely, the human brain is less prone to recovery than the mouse brain. Therefore, there is a need to develop approaches to screening human tissue and identifying factors that prevent endogenous neurogenesis.

Therapeutic manipulations in vivoEven if we manage to overcome all the problems listed above, we will have to solve the problem of developing strategies for minimally invasive manipulation of human brain cells.

To date, the best strategy is pharmacological therapy. However, reprogramming NSCs into new types of neurons will require the introduction of DNA or other genetic material into cells. When working with rodents, this strategy is applied to certain types of cells using technologies for creating transgenic animals, viral gene delivery, electroporation, delivery systems based on nanoparticles or exosomes, as well as, to a certain extent, with the help of peptides penetrating into cells. The use of nanoparticles and exosomes can theoretically be applied in the clinic. Especially attractive and in need of careful study is the method of noninvasive intranasal administration. The successful development of in vivo delivery systems suitable for clinical use requires the joint work of biologists and specialists in the field of bioengineering.

ConclusionDespite the difficulties listed above and the long duration of the period required to develop effective methods of restoring the brain and improving cognitive abilities, we cannot refuse to conduct research in the four directions outlined above.

Over the past decade, there has been an exponential increase in the number of studies devoted to the study of "adult neurogenesis".

In general, the currently active study of stem cell biology and the development of systems for delivering therapeutic drugs to brain tissue should shed light on the processes of brain development and endogenous responses to damage, as well as give rise to new approaches to brain regeneration and restoration of cognitive functions that have deteriorated due to brain injuries and neurodegenerative diseases. A prerequisite is also to verify the applicability of the results obtained in experiments on animal models in clinical conditions.

List of literature:Basak, O., and Taylor, V. (2009).

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