VEGF preconditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis

Abstract

Several factors are known to enhance adult hippocampal neurogenesis but a factor capable of inducing a long-lasting neurogenic enhancement that attenuates age-related neurogenic decay has not been described. Here, we studied hippocampal neurogenesis following conditional VEGF induction in the adult brain and showed that a short episode of VEGF exposure withdrawn shortly after the generation of durable new vessels (but not under conditions where newly made vessels failed to persist) is sufficient for neurogenesis to proceed at a markedly elevated level for many months later. Continual neurogenic increase over several months was not accompanied by accelerated exhaustion of the neuronal stem cell (NSC) reserve, thereby allowing neurogenesis to proceed at a markedly elevated rate also in old mice. Neurogenic enhancement by VEGF preconditioning was, in part, attributed to rescue of age-related NSC quiescence. Remarkably, VEGF caused extensive NSC remodelling manifested in transition of the enigmatic NSC terminal arbor onto long cytoplasmic processes engaging with and spreading over even remote blood vessels, a configuration reminiscent of early postnatal "juvenile" NSCs. Together, these findings suggest that VEGF preconditioning might be harnessed for long-term neurogenic enhancement despite continued exposure to an "aged" systemic milieu.adult neurogenesis | VEGF | neurovascular | aging | neural stem cells T he reserve of neuronal stem cells (NSCs) in the hippocampal dentate gyrus (DG) continues to produce neuroblasts maturing into functional neurons after birth. Adult hippocampal neurogenesis, however, rapidly declines with age, and in the rodent brain, it is barely detected beyond 8 mo of age (1-4). Several factors, including BDNF, FGF, insulin-like growth factor, VEGF, and others, were shown to enhance the basal level of hippocampal neurogenesis (reviewed in ref. 5). However, there is no report of a factor capable of inducing sustained neurogenic enhancement lasting months after its withdrawal.It has been shown that age-related decrease in hippocampal neurogenesis is associated with progressive depletion of the finite NSC pool due to the fact that neuroblast-producing asymmetrical NSC divisions can only take place a limited number of times before their terminal differentiation to astrocytes (2). Supporting the notion of an exhaustible NSC reservoir is also a study showing that experimentally forced accelerated neurogenesis results in premature NSC depletion (6) and a study showing that experimentally induced epilepsy is associated with premature NSC exhaustion (7). Balancing this deterministic view, however, certain genetic manipulations [e.g., experimental phosphatase and tensin homolog (PTEN) deletion] were shown to increase NSC number by symmetrical divisions (8). It thus remains unclear whether there are means to enforce enhanced hippocampal neurogenesis for a long period without necessarily causing premature exhaustion of the NSC reservoir and a resultant accelerated age-related neurogenic decay.

On the Run for Hippocampal Plasticity

“…Vascular endothelial growth factor (VEGF) may mediate exercise-induced vascular plasticity, adult neurogenesis, and communication between peripheral tissues and brain (Carmeliet 2003; Fabel et al 2003; Cotman et al 2007; Udo et al 2008). VEGF is involved in blood vessel formation (Prior et al 2003; Gavin et al 2004; Kraus et al 2004) and can attenuate the aged-related decline in neurogenesis (Licht et al 2016). The importance of VEGF for neurogenesis was first shown in songbirds.…”

Early Stem Cell Aging in the Mature Brain

“…Some NSCs are short-lived and divide rapidly to mainly produce granule neuronsexhibiting "division-coupled differentiation" behavior (Encinas et al, 2011) or "developmental-like model" behavior (Pilz et al, 2018). Meanwhile, some studies (Bonaguidi et al, 2011;Dranovsky et al, 2011;Jang et al, 2013;Licht et al, 2016) have advanced a stem cell maintenance model where NSCs are longer lived, slowly cycle in and out of quiescence, can generate neurons, astrocyte and self-renew. We reasoned that cellular heterogeneity within the radial glial-like NSC pool masks the ability to precisely uncover which mechanisms contribute to NSC dysfunction over time (Bonaguidi et al, , 2016.…”

“…Consistently, forced accelerated neurogenesis (Ehm et al, 2010;Jones et al, 2015;Renault et al, 2009) and pathological conditions (Mu and Gage, 2011;Sierra et al, 2015) can result in premature NSC depletion. In another scenario, studies (Bonaguidi et al, 2011;Dranovsky et al, 2011;Licht et al, 2016) have shown that self-renewing NSCs are maintained and neurogenesis instead could decline during aging due to an increase in NSC quiescence (Hattiangady and Shetty, 2008;Ziebell et al, 2018). While NSCs as a population clearly undergo early age-related changes, when and how specific NSC subpopulation begin to exhibit dysfunction remain unclear.…”

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

“…Since norvaline elevates NOS3 levels [16], we suggest a significant involvement of VEGF activation in the phenotype observed following norvaline treatment. VEGF is essential for neuroprotection [22], and its activation is beneficial for individuals with early signs of AD-associated dementia [23].VEGF preconditioning has been shown to attenuate age-related decay of adult hippocampal neurogenesis in mice [24]. Additionally, the administration of VEGF in rats with focal cerebral ischemia reduces the infarct size and enhances neurogenesis [25].…”

“…VEGF preconditioning has been shown to attenuate age-related decay of adult hippocampal neurogenesis in mice [24]. Additionally, the administration of VEGF in rats with focal cerebral ischemia reduces the infarct size and enhances neurogenesis [25].…”