Oxidative-Signaling in Neural Stem Cell-Mediated Plasticity: Implications for Neurodegenerative Diseases

Abstract

The adult mammalian brain is capable of generating new neurons from existing neural stem cells (NSCs) in a process called adult neurogenesis. This process, which is critical for sustaining cognition and mental health in the mature brain, can be severely hampered with ageing and different neurological disorders. Recently, it is believed that the beneficial effects of NSCs in the injured brain relies not only on their potential to differentiate and integrate into the preexisting network, but also on their secreted molecules. In fact, further insight into adult NSC function is being gained, pointing to these cells as powerful endogenous "factories" that produce and secrete a large range of bioactive molecules with therapeutic properties. Beyond anti-inflammatory, neurogenic and neurotrophic effects, NSC-derived secretome has antioxidant proprieties that prevent mitochondrial dysfunction and rescue recipient cells from oxidative damage. This is particularly important in neurodegenerative contexts, where oxidative stress and mitochondrial dysfunction play a significant role. In this review, we discuss the current knowledge and the therapeutic opportunities of NSC secretome for neurodegenerative diseases with a particular focus on mitochondria and its oxidative state.

Keywords: antioxidant; degenerative diseases; mitochondrial dysfunction; neural stem cells; oxidative stress; regeneration; secretome.

Figure 1

Oxidative stress and mitochondrial dysfunction loop. Along with endogenous sources, several environmental and exogenous stressors may lead to an excessive generation of mitochondrial ROS. The higher ROS levels, in turn, promote mitochondria injury, alter their metabolic enzymes and lead to its further dysfunction. In this way, mitochondrial oxidative stress can be the cause and consequence of mitochondrial dysfunction, being involved in the pathogenesis of several neurodegenerative diseases.

Figure 2

Antioxidative mechanisms triggered by secreted neurotrophic factors. It has been shown that neurotrophic factors act in major antioxidant defense pathways, rescuing target cells from oxidative damage. The underlying mechanisms of this process involve upregulation of antioxidative proteins/enzymes, increase of their activation levels, alteration in Ca²⁺ homeostasis, activation of signaling pathways, changes in mitochondrial morphology and dynamics, among others. mt., mitochondria.

Figure 3

Biogenesis and release of stem cell-derived exosomes. Endosomes are produced through invaginations of the plasma membrane, which in turn generate intraluminal vesicles by budding into early endosomes and multivesicular bodies (MVBs). Through the endosomal sorting complex required for transport pathways, exosomes are formed and packaged within endosomes. Some of the MVBs fuse with lysosomes to form the endolysosome, where all components are digested, while others fuse with the plasma membrane resulting in exosome release into the extracellular space. This image was created with BioRender.com.

Figure 4

Mitochondrial transfer via tunneling nanotubes. Under certain circumstances, cells are capable of sending mitochondria to recipient cells through nanotubular actin-based structures. The donor cell extends a filopodia-like protrusion toward the recipient cell, forming a strait connected bridge between cells, in which the transfer is feasible in both directions. Miro1, a protein that is anchored to the outer mitochondrial membrane, binds to the motor proteins kinesin and dynein, and promotes mitochondrial transfer, leading to the restoration of aerobic respiration and improvement of target cell survival. This image was created with BioRender.com.