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Review

Neural Stem Cells and Nutrients: Poised Between Quiescence and Exhaustion Virve Cavallucci,1,z Marco Fidaleo,1,z and Giovambattista Pani1,* Adult neurogenesis initiated by neural stem cells (NSCs) contributes to brain homeostasis, damage repair, and cognition. Energy metabolism plays a pivotal role in neurogenic cell fate decisions regarding self-renewal, expansion and multilineage differentiation. NSCs need to fine-tune quiescence and proliferation/commitment to guarantee lifelong neurogenesis and avoid premature exhaustion. Accumulating evidence supports a model whereby calorie restriction or increased energy expenditure reinforce NSC quiescence and promote self-renewal. Conversely, growth/proliferation inputs and anabolic signals, although necessary for neurogenesis, deplete the NSCs pool in the long run. This framework incorporates the emerging neurogenic roles of nutrient-sensing signaling pathways, providing a rationale for the alarming connection between nutritional imbalances, metabolic disorders and accelerated brain aging. Slow and Steady Wins the Age. . . Adult stem cells are defined based on their properties of long-term self-renewal, extensive proliferative capacity, and competence for regenerating the multiple differentiated cell lineages of their tissue of origin [1]. Although a high replicative potential is a hallmark of stemness, a near unique characteristic of adult stem cells is their capacity to remain quiescent (i.e., nondividing) for long periods up to a lifetime, thus providing a regenerative reserve available for tissue repair or replacement of age-related cell loss [2].

Trends Quiescent stem cells, including quiescent neural stem cells (qNSC), recapitulate many aspects of hypometabolic, reversibly growth-arrested, and longlived states of simple organisms. Nutrient signals and energy metabolism control adult neurogenesis at different levels, and in particular regulate NSC transition between quiescent and activated states. Converging evidence from genetic and nutritional studies indicate that deregulated nutrient signaling leads to abnormal and wasteful NSC activation followed by premature exhaustion. NSC exhaustion is a major component of brain aging and related disease, and may explain the connection between metabolic disorders and cognitive impairment.

It is still unclear how a stem cell quiescent state is actively maintained, and what are the responsible signals, molecular cascades, and cellular interactions. Stem cell quiescence (see Glossary) resembles many aspects of growth-arrested cell states associated with extended longevity in model organism, namely G0 arrest in stationary-phase Saccharomyces cerevisiae (baker's yeast) and dauer/larva arrest in nematodes (Figure 1). These long-lived states are largely dictated by the availability of nutrients and the cell and non-cell-autonomous signals they deliver to cells. Likewise, metabolic cues, such as calorie restriction or increased energy expenditure due to physical exercise, act as important determinants of stem cell fate in mammals, through evolutionarily conserved energy-sensing circuitries, such as the insulin-IGF pathway or the NAD+[12_TD$IF]-dependent sirtuin deacetylases with their substrates [3]. A ‘standby’ mode preserves stem cells from uncontrolled expansion and premature exhaustion, while leaving them poised to reactivate upon demand [4]. Interestingly, highly proliferating phases of both embryonic and adult stem cells are associated with hyperglycemic conditions as seen in gestational diabetes, trauma-induced inflammation, or physical stress. Moreover, excess nutrients or overactivation of the nutrient-sensitive signaling cascades accelerate depletion of adult stem cell populations from tissues as diverse as brain, skin, muscle, and bone

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1 Institute of General Pathology, Università Cattolica School of Medicine, 00168 Rome, Italy z These authors contributed equally to this work.

*Correspondence: [email protected] (G. Pani).

http://dx.doi.org/10.1016/j.tem.2016.06.007 © 2016 Elsevier Ltd. All rights reserved.

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Figure 1. Stem Cell Quiescence, a Model of Longevity?. In laboratory conditions, limited nutrient supply is associated with cell quiescence, increased stress resistance and extended lifespan in a fashion that is evolutionarily conserved from yeast, to invertebrates, to mammalian adult stem cells. Nutrient-sensitive pathways and metabolic programs involved in the long-term maintenance of the neural stem cell pool recapitulate several molecular paradigms of extended longevity in model organisms. Abbreviation: IIS, insulin/IGF-I signaling.

marrow [5–8]. Conversely, low glucose or nutrient restriction limit stem cell pool expansion and commitment to differentiation [9]. The present article focuses on the metabolic regulation of adult neural stem cells (NSCs), and in particular on the emerging role of nutrients and energy metabolism in the transition between NSC quiescence and neurogenic activation, and on the underlying molecular cascades. This represents the first level of neurogenesis control and it is increasingly recognized that its derangement can lead to premature NSC depletion. In turn, stem cell exhaustion in the brain as in other tissues may contribute to age-related functional decline and disease [10]. Some of the nutrient-dependent signals discussed here also affect equally important aspects of adult neurogenesis, such as multilineage differentiation, migration of newborn cells and their integration into

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Agouti-related peptide (AgRP)/ neuropeptide Y (NPY): orexigenic neuropeptides released by AgRP/ NPY neurons that reside in the arcuate nucleus of the hypothalamus. Brain-derived neurotrophic factor (BDNF): trophic and pro-neurogenic factor belonging to the neurotrophin family of growth factors. They act on several neurons of the central and peripheral nervous system. Calorie (or dietary) restriction: reduction of calorie intake without malnutrition. g-Aminobutyric acid (GABA): the main inhibitory neurotransmitter of mammalian CNS. Hairy and enhancer of split-1 (Hes-1): a repressor-type basic helixloop-helix (bHLH) transcriptional factor repressing genes that require a bHLH protein for their transcription. Insulin-like growth factor I (IGF-I): a polypeptide hormone with high sequence similarity to insulin. IGF-I is produced by the liver in proportion to systemic availability of amino acids. Mammalian target of rapamycin (mTOR): a serine/threonine kinase and the catalytic subunit of two distinct molecular complexes, mTORC1 and mTORC2, the first of which is specifically involved in amino acid and energy sensing and is inhibited by rapamycin. Neurospheres: free-floating cell clusters generated in vitro by neural stem cells and comprising NSCs and their progeny. Neurosphere assay (NSA) provides a method to evaluate the frequency and self-renewal capacity of NSCs based on the number and size of neurospheres formed by seeding a dissociated neurogenic tissue in a highly defined, growth factor-enriched medium. N-Methyl-D-aspartate (NMDA) receptors: ionotropic glutamate receptors largely expressed in the CNS. NADPH-dependent oxidases (NOXs): enzymes that assemble on the membrane of phagocytic and nonphagocytic cells in response to external stimuli to generate superoxide (O2ˉ) by incomplete reduction of molecular oxygen. Quiescence: a cell state characterized by cell cycle arrest, enhanced stress resistance, extended longevity and reduced transcriptional, translational and metabolic activity.

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preexisting circuitries. These additional aspects will be only touched upon in the present article, but without a doubt the downstream flow between stem, precursor, and terminally differentiated cell compartments is also crucial for lifelong maintenance of organ function. This is particularly important in the brain, where the cycles of cell replacement are relatively slow compared to, for instance, epidermis, gut epithelia, or blood cells.

Adult Neurogenesis Neurogenesis is the generation and maturation of new neurons from NSCs and their derivative progenitors. Besides playing a central role in the developing central nervous system (CNS), neurogenesis continues to be active throughout the adult life [11]. As for many other types of stem cells, the fate of NSCs is constantly and finely regulated by changes in the microenvironment, the ‘niche’, in which they reside (Box 1). These changes are dictated by both intrinsic (e.g., hormones, cytokines, neurotrophins, and growth factors) and extrinsic (e.g., stress, aging, physical activity, environmental enrichment) factors [11]. Adult neurogenesis in the mammalian brain occurs mainly in the subventricular zone (SVZ) of the lateral ventricles and in the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus, leading to the formation of, respectively, new olfactory bulb interneurons and new granule cells. More recently, the hypothalamus has been identified as a third important neurogenic area in the mammalian brain [12,13] (see Figure I in Box 1).

Sirtuins: a family of proteins with mono-ADP-ribosyltransferase or deacylase activity that orchestrate cell and tissue adaptation to different kinds of stressful conditions, including nutrient restriction, through a host of genetic and epigenetic mechanisms. Synaptic plasticity: experiencedependent change in the efficacy of synaptic transmission that underlies learning and memory formation. The best-studied forms of synaptic plasticity are long-term potentiation (LTP) and long-term depression (LTD), namely the activity-dependent strengthening and weakening of synapses, respectively. Transit-amplifying cells (TAC): also known as neural progenitor cells (NPC), are differentiation committed cells derived from the asymmetric division of stem cells and endowed by elevated proliferative but no selfrenewal capacity.

Functions of NSCs: Homeostasis, Repair, Cognition Enhanced proliferation and differentiation of NSCs is induced by different types of CNS damage, including mechanical, excitotoxic, and ischemic injury [14,15] (Figure 2A, Key Figure). However, functions of adult neurogenesis may go well beyond the provision of a simple cellular backup system for replacement of cell loss and tissue repair. For instance, in the olfactory bulb, interneurons generated in adulthood are involved in olfactory learning [16,17]; likewise, neurogenesis in the DG contributes to memory formation and to the plasticity of neural circuits, as demonstrated by many studies that correlate the increase of neurogenesis with improved behavioral performance [18]. It is also well known that some activities that promote learning and memory, such as physical exercise and exposure to an enriched environment, promote hippocampal neurogenesis [19,20] (Figure 2A), and that the number of newborn neurons in the DG correlates with preservation of hippocampal-dependent spatial learning performances in aged rats [21]. Intriguingly, newborn neurons that participate in the formation of new memories in the hippocampus also contribute to the extinction (forgetting) of old ones [22]. These remarkable functional properties likely reflect an elevated degree of synaptic plasticity of immature cells; indeed, electrophysiological studies revealed that their enhanced long-term potentiation (LTP) is dependent on the subunit composition of NMDA receptors [23] and on the temporary resistance to the inhibitory effect of GABA [24]. Adult neurogenesis in the hypothalamus is involved in the control of energy balance and body weight homeostasis. It has been demonstrated that cell proliferation and generation of new neurons expressing the orexigenic neuropeptides agouti-related peptide (AgRP)/ neuropeptide Y (NPY) counters the progressive degeneration of preexisting AgRP/NPYpositive cells, thus preserving appetite and energy homeostasis in aged rodents [25]. Reciprocally, energy-balance disorders can affect adult hypothalamic neurogenesis. For instance, a reduction of neurogenesis in the arcuate nucleus, in part caused by an increase of apoptosis of newborn neurons, has been described in obese mice fed a high fat diet (HFD). Conversely, calorie restriction can rescue hypothalamic neurogenesis in obese mice [26].

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Box 1. Neurogenic Areas of the Adult Brain The subventricular zone (SVZ), along the walls of lateral ventricles, is the biggest germinal zone present in the adult brain [88,89] (Figure I). Stem cells within SVZ are referred to as type B cells and are glial fibrillary acidic protein (GFAP)expressing astrocyte-like cells displaying functional characteristics intermediate between radial glia and astrocytes [90]. Type B cells divide slowly and generate transit-amplifying [1_TD$IF]cells (type C cells) that in turn proliferate to produce neuroblasts (type A cells) or glia. Then, neuroblasts migrate from the SVZ along the rostral migratory stream (RMS) to the olfactory bulb where most of them become granule cells while a small part generates periglomerular cells [91]. The dentate gyrus (DG) is the hippocampal region that receives inputs from the enthorinal cortex and sends outputs to the hippocampal CA3 field. Adult neurogenesis in the subgranular zone (SGZ) of the DG implies the activation of type 1 NSCs, mainly quiescent astrocyte-like stem cells similar to the type B cells of SVZ, to generate proliferative type 2 cells (transitamplifying [1_TD$IF]cells) that can be subdivided into type 2a and type 2b. These last are lineage-committed proliferative neuronal precursors that produce differentiating neuroblasts (type 3 cells). Neuroblasts migrate into the inner granule cell layer where they mature into dentate granule neurons that extend dendrites to the molecular layer and prolong axons to the CA3 [92]. Importantly, SGZ and SVZ present characteristic vascular plexi and NSCs are concentrated around blood vessels with lax blood-brain barrier (BBB), that allows their constant contact with circulating molecules and nutrients [93]. Accordingly, hippocampal neurogenesis induced by running activity is associated with an increase of cerebral blood volume in the DG [94]. ‘Non-canonical’ adult neurogenesis also occurs in the hypothalamus, a small region of the brain surrounding the third ventricle with a key role in homeostatic regulation of many body functions. Tanycytes have been identified as hypothalamic stem cells; these non-ciliated ependymal cells with radial glia-like features are in contact with the cerebrospinal fluid (CSF) and extend long cell processes into the hypothalamic parenchyma. Tanycytes are classified into four types based on their position along the 3rd ventricle wall (/1-, /2-, b1-, and b2-tanycytes); no consensus exists yet regarding which types of tanycytes are the true adult hypothalamic NPCs [95].

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Figure I. Neurogenic Areas in Adult Brain. Parasagittal view of adult mouse brain depicting the three main neurogenic areas: the hippocampal dentate gyrus (DG), the subventricular zone (SVZ) of the lateral ventricle, and the hypothalamus. Maturation stages from NSC to neurons are schematized in color boxes (Green = DG, Red = SVZ). A coronal view of the hypothalamus with the different types of tanycytes along the third ventricle (3V) is also shown (brown box). Abbreviations: ME, median eminence; OB, olfactory bulb; RMS, rostral migratory stream.

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Figure 2. Regulation and Fate Decision of NSCs. (A) Schematic representation of external stimuli (as brain injury, physical exercise, and nutrients) and molecular players affecting NSC decision between quiescent and active state. Two potential fates after NSC activation, self-renewal versus expansion/commitment, are indicated. (B) Nutrient sensors and pathways regulating metabolic homeostasis in NSCs. Maintenance of quiescence by starvation involves downregulation of the insulin/IGF and mTOR cascades, and activation of CREB and sirtuins, that overall promote glycolysis and fatty acid catabolism. The opposite signaling pattern is activated under nutrient replenishment, leading to ribosome biogenesis, protein synthesis, mitochondrial oxidative phosphorylation and fatty acid synthesis, as observed in aNCSs and subsequent differentiating stages. Abbreviations: FAO, FA oxidation; NPCs, neural progenitor cells; NSC, neural stem cell; ROS, reactive oxygen species; TACs, transit-amplifying cells.

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Metabolic Control of NSC Fate Because stem cells preferentially utilize aerobic glycolysis, as opposed to their more differentiated progeny that generates ATP mainly by mitochondrial oxidative phosphorylation [27], the regulation of energy metabolism is a crucial player in stem cell fate determination. Consistent with this being true also for NSCs, rodents subjected to calorie restriction display increased numbers of newly produced neural cells in the SGZ and higher expression of brain-derived neurotrophic factor (BDNF) [28]. [13_TD$IF]By [14_TD$IF]contrast, adult neurogenesis is impaired in several rodent models of diet-induced obesity and diabetes [29]. More recently, a host of mouse mutants harboring defects that up- or down-regulate nutrient-triggered signals have been reported to display aberrant adult neurogenesis (see later), confirming that nutrient-regulated switches participate in NSC fate decisions. Among these decisions, the transition between the quiescent and activated states is particularly critical, as it requires cell entry into the cell cycle that is a major energetic commitment (Box 2). Glycolysis versus Oxidative Metabolism NSCs reside in niches characterized by low oxygen tension (