Lysosomes and signaling pathways for maintenance of quiescence in adult neural stem cells

Abstract

Quiescence is a cellular strategy for maintaining somatic stem cells in a specific niche in a low metabolic state without senescence for a long period of time. During development, neural stem cells (NSCs) actively proliferate and self-renew, and their progeny differentiate into both neurons and glial cells to form mature brain tissues. On the other hand, most NSCs in the adult brain are quiescent and arrested in G0/G1 phase of the cell cycle. Quiescence is essential in order to avoid the precocious exhaustion of NSCs, ensuring a sustainable source of available stem cells in the brain throughout the lifespan. After receiving activation signals, quiescent NSCs reenter the cell cycle and generate new neurons. This switching between quiescence and proliferation is tightly regulated by diverse signaling pathways. Recent studies suggest significant involvement of cellular proteostasis (homeostasis of the proteome) in the quiescent state of NSCs. Proteostasis is the result of integrated regulation of protein synthesis, folding, and degradation. In this review, we discuss regulation of quiescence by multiple signaling pathways, especially bone morphogenetic protein and Notch signaling, and focus on the functional involvement of the lysosome, an organelle governing cellular degradation, in quiescence of adult NSCs.

A Shift in Tissue Stiffness During Hippocampal Maturation Correlates to the Pattern of Neurogenesis and Composition of the Extracellular Matrix

“…Neurogenesis in the DG of the hippocampus is observed throughout the lifetime of mammals, and the differentiation of NSCs in the hippocampus can be dependent on the tissue environments, including mechanical cues (Urban et al, 2019;Kobayashi and Kageyama, 2021). Indeed, several in vitro studies have shown that mechanical stiffness affects the migration and differentiation of NSCs (see ''Introduction'' section).…”

“…Previous studies have reported on heterogeneous tissue stiffness in the rodent hippocampus at the neonatal, juvenile, and adult stages (Elkin et al, 2010;Antonovaite et al, 2021). Based on such findings, it is deduced that the stiffness may be related to the niche of NSCs and their activity, including the maintenance and regulation of NSCs (Urban et al, 2019;Kobayashi and Kageyama, 2021). Indeed, it is reported that the mechanical stiffness of the stem cell niche in the SVZ can regulate NSC activity (Kjell et al, 2020).…”

Novel Roles of Small Extracellular Vesicles in Regulating the Quiescence and Proliferation of Neural Stem Cells

“…NSCs, which are derived from the neuroepithelium of the neural tube, maintain the ability to self-renew and to give rise to neurons, astrocytes, and oligodendrocytes throughout a whole life. Two generally accepted canonical domains in the adult central nervous system that keep a reservoir of NSCs are the subventricular zone near the lateral ventricles and the subgranular zone of the dentate gyrus, where most of the NSCs remains quiescent ( Cheung and Rando, 2013 ; Urban et al, 2019 ; Kobayashi and Kageyama, 2021 ). The quiescent state of NSCs, which is characterized by low metabolic rate and low protein and RNA synthesis, is vital to the preservation of their genomic integrity and essential functional properties ( Cavallucci et al, 2016 ).…”

Novel roles of small extracellular vesicles in regulating the quiescence and proliferation of neural stem cells

“…NSCs, which are derived from the neuroepithelium of the neural tube, maintain the ability to selfrenew and to give rise to neurons, astrocytes, and oligodendrocytes throughout a whole life. Two generally accepted canonical domains in the adult central nervous system that keep a reservoir of NSCs are the subventricular zone near the lateral ventricles and the subgranular zone of the dentate gyrus, where most of the NSCs remains quiescent (Cheung and Rando, 2013;Urban et al, 2019;Kobayashi and Kageyama, 2021). The quiescent state of NSCs, which is characterized by low metabolic rate and low protein and RNA synthesis, is vital to the preservation of their genomic integrity and essential functional properties (Cavallucci et al, 2016).…”