Neurogenesis and aging: FGF‐2 and HB‐EGF restore neurogenesis in hippocampus and subventricular zone of aged mice

“, 2007), administration of neurotrophic factors such as FGF-2 and IGF-1 (Lichtenwalner et al., 2001; Jin et al., 2003; Rai et al., 2007), regular physical exercise (Arida et al.”

“Supporting a role for environmental cues in the age-associated decline in neurogenesis, it was shown that exogenous addition of growth factors such as insulin-like growth factor I (IGF-I) (Lichtenwalner et al 2001), epidermal growth factor (EGF) and fi broblast growth factor (FGF-2) (Jin et al 2003) or a reduction of c…”

“…in the SVZ was shown to be increased by a variety of growth factors and hormones, including epidermal growth factor (EGF), fibroblastic growth factor (FGF), vascular endothelial growth factor (VEGF) and thyroid hormone (Doetsch et al., 2002a,b; Jin et al., 2002, 2003; Lemkine et al., 2005).”

“The neurogenesis can be increased or even restored to young adult levels by an enriched environment (Kempermann et al., 2002), infusion of growth factors (Jin et al., 2003), stroke (Jin et al., 2004b; Darsalia et al., 2005), or seizures (Gray et al., 2002).”

“We found previously that HB-EGF stimulates neurogenesis in vitro and in SVZ and SGZ in adult (Jin et al., 2002) and aged (Jin et al., 2003b) rat brain in vivo.”

“Specifically, there is an 80% reduction in the rate of neural stem/progenitor cell (NPC) proliferation in the dentate gyrus of aged brains (Jin et al., 2003).”

“Similar age-dependent decrease in neurogenesis has been shown to occur in the SVZ [399-401].”

“…brainderived neurotrophic factor (BDNF), fibroblast growth factor (FGF), insulin-like growth factor, vascular endothelial growth factor, and glial cell line-derived neurotrophic factor (GDNF) (Aberg et al., 2000; Jin et al., 2003; Newton and Duman, 2004; Chen et al., 2005; Scharfman et al., 2005).”

“We found previously that, notwithstanding an age-related decrement in basal endogenous neurogenesis (Jin et al., 2003a) and, in some cases, an age-dependent increase in stroke size (Jin et al., 2010b), aged rats retain the ability to respond to either growth factors (Jin et al., 2003a) or cerebral…”

“This finding, together with a previous study that reported increased hippocampal neurogenesis following intraventricular infusion of FGF2 to old rats (Jin et al., 2003), suggests first that FGFs act directly on hippocampal stem cells and second that the decrease in neurogenesis with age is not only due to a decreased…”

“HB-EGF is expressed in the embryonic VZ/SVZ (Nakagawa et al., 1998) and promotes neurogenesis in the adult CNS (Jin et al., 2003).”

“It has been shown that by increasing pro-neurogenic factors or decreasing antineurogenic factors, it is possible to change the number of proliferating NPCs, suggesting that the impaired proliferation in the aged brain results from changes in the neurogenic niche [34, 40].”

“N IH -PA Author M anuscript N IH -PA Author M anuscript et al., 1997; Wagner et al., 1999), heparin-binding EGF (HB-EGF) (Jin et al., 2002b), stem cell factor (SCF) (Jin et al., 2002a) and vascular endothelial growth factor (Jin et al., 2002c).”

“A substantial number of experiments were performed to study the effects of the three factors on neurogenesis during adulthood or aging indicating a strong positive effect on NSCs proliferation by IGF-1 [93-95], FGF-2 [96-100], and VEGF [101104] signaling, with the latter also resulting in improved spatial memory funct…”

“A proliferative stem cell niche, the subventricular zone (SVZ), is also maintained along the lateral wall of the lateral ventricles in the adult mouse brain (Doetsch et al., 1997; Tropepe et al., 1997; Jin et al., 2003; Enwere et al., 2004; Maslov et al., 2004; Conover & Shook, 2011; Shook et al., 2012), and SVZ stem…”

“This provides more evidence that the stem cells themselves are not intrinsically different, but are responding to their changed environment (Jin et al. 2003).”

“Recent studies show that neurogenesis diminishes with aging [19,20,21,22], and this limit the suitability of the aged brain as a target for cell replacement therapy.”

“…have been implicated in neurogenesis including neurotransmitters (Santarelli et al., 2003; Jiang et al., 2005), growth factors (Kuhn et al., 1997; Doetsch et al., 2002; Jin et al., 2003; Ghashghaei et al., 2007; Zhao et al., 2007) and cytokines (Ekdahl et al., 2003; Butovsky et al., 2006).”

“For example, there is good consensus that SVZ cell proliferation is decreased by © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd European Journal of Neuroscience, 37, 1978–1986 50–70% (Ki67, BrdU) at 10–14 months of age (Luo et al., 2006; Tanaka et al., 2007; Belluardo et al., 2008; Boua…”

“…neural activity are positive regulators of neurogenesis (Kempermann et al., 1998, 2002; Gould, 1999; Nilsson et al., 1999; van Praag et al., 1999, 2005; Lichtenwalner et al., 2001; Jin et al., 2002, 2003; Sun et al., 2003, 2006; Mirescu et al., 2004; Sairanen et al., 2005; Rai et al., 2007).”

“Neurogenesis in the dentate gyrus decl ines with age [7 ] , and environmental enrichment [32] or replenishment of growth factors [33, 34] are reported to partly recover the decline in the number of new neurons in the dentate gyrus.”

“EGF has been shown to promote neurogenesis and is involved in the neuroendocrine response to stress [109, 110].”

“The newborn cells can migrate into the damaged brain regions (Jin et al., 2003b), express phenotypic markers of mature neurons (NeuN, MAP-2) and region-specific mature neuronal markers like dopamine (Arvidsson et al., 2002; Parent et al., 2002), and form synapses (Yamashita et al., 2006).”

“…factor (Wagner et al., 1999; Cheng et al., 2002), intracerebroventricular fibroblast growth factor and heparin-binding epidermal growth factor (Jin et al., 2003) and insulin-like growth factor I (Aberg et al., 2000; O’Kusky et al., 2000; Lichtenwalner et al., 2001; Trejo et al., 2001; Aberg…”

“mice results in an augment of BrdU-positive cells in both neurogenic niches (Jin et al., 2003).”

“18 mm rostral from bregma (contains SVZ based on mouse brain atlas) (Jin et al., 2003).”

“Aβ, amyloid peptides; AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; BMPs, bone morphogenetic proteins; DGCs, dentate granule cells; DISC1, Disrupted-in-Schizophrenia-1; ESCs, embryonic stem cells; FD, familial dysautonomia; FGF, fibroblast growth factor; GWAS, genome-wide…”

“However, a variable but substantial proportion of NSCs is preserved in both the SGZ and SVZ of old mice, but these are dormant rather than senescent and can be reactivated (Jin et al., 2003; Hattiangady and Shetty, 2008; Lugert et al., 2010; Giachino et al., 2014).”

“In the adult rodent, the majority of SVZ cells coexpress both FGF2 and EGF receptors [87, 91].”

“…the aged brain preserves to a certain extent the ability to respond with increased neurogenesis to injury (Jin et al., 2004), environmental enrichment (Kempermann et al., 1998), hormonal manipulation (Cameron & McKay, 1999), growth factors (Jin et al., 2003a) and seizures (Gray et al., 2002).”

“REVIEW published: 14 April 2015 doi: 10.3389/fncel.2015.00140 Edited by: Dirk M. Hermann, University Hospital Essen, Germany Reviewed by: Luca Peruzzotti-Jametti, University of Cambridge, UK Maria Vittoria Podda, Università Cattolica del Sacro Cuore, Italy Marta Pace, University of Bern, Switzerland *Correspondence: O…”

“, 1996), and intracerebroventricular FGF-2 infusion counteracts this reduced neurogenesis (Jin et al., 2003).”

“In parallel, in the aged brain, both the pool of NSC and their proliferative potential are markedly diminished [ 38-40 ].”

“IGF1, IGF2, EGF, FGF2, VEGF and WNT3 are reduced with age in the NSC niche, and enhancing some of these signals can rejuvenate the niche in aged animals, at least to some extent (Enwere et al., 2004; Jin et al., 2003; Kang and Hebert, 2015; Licht et al., 2016; Lichtenwalner et al., 2001; Miranda et al., 2012; Okamoto…”

“Hb-egf has been implicated in neurogenesis during retinal regeneration in zeb-ra fi sh using morpholino knockdown techniques 32 , and it has also been reported to induce neurogenesis in the hippocampal subventricular zone and dentate gyrus in mice and rats 33,34 .”

“Extrinsic factors regulating the development of neural progenitors within the SGZ include Shh [3,4], Wnt [5], EGF [6], FGF-2 [7] and VEGF [8].”

“…changes including decreased expression of growth factors that support proliferation and neurogenesis, such as vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and insulin-like growth factor-1 (IGF-1) (Jin et al., 2003; Schanzer et al., 2004; Sonntag et al., 2005).”

“Stem cells are also present in two distinct niches in the adult mammalian brain, the subventricular zone and the subgranular zone (SGZ) of the hippocampus (Jin et al. 2003; Navarro-Quiroga et al. 2006; Tanaka et al. 2007; Valente et al. 2009).”

“…applied to cultures derived from the adult hippocampus (Vescovi et al., 1993; Gage et al., 1995; Palmer et al., 1995), and increases neurogenesis in the dentate gyrus and subependymal zone upon infusion into the brain (Kuhn et al., 1997; Tao et al., 1997; Wagner et al., 1999; Jin et al., 2003).”

“ubiquitous and life-long role in neurogenesis [6,7] in adult rat.”

“, KAPLAN, R.A. and LUO, J. (2005) Developmental expression of matrix metalloproteinases 2 and 9 and their potential role in the histogenesis of the cerebellar cortex.”

“The activation of P4R increases the expression level of ERK to promote the neurogenesis in adult and aged rodent brains (Cheng et al., 2001; Jin et al., 2003).”

“…and macaques (Seki and Arai, 1995; Kuhn et al., 1996; Kempermann et al., 1998; Cameron and McKay, 1999; Gould et al., 1999a; Lemaire et al., 2000; Jin et al., 2003; Nacher et al., 2003; Heine et al., 2004; McDonald and Wojtowicz, 2005; Simon et al., 2005; Kronenberg et al., 2006; Rao et al.,…”

“Newly generated neurons can migrate into damaged brain regions after cerebral ischemia (Nakatomi et al., 2002; Jin et al., 2003a) and may be capable of replacing damaged cells because they can differentiate into mature, functional neurons (Shors et al., 2001).”

“3d), as shown previously 56,58 .”

“by neurotrophic factors is necessary [30].”

“However, expansion strategies for adult neural stem cells may be important to overcome the severe decline in adult neural stem cell numbers in older and aging brains (Jin et al., 2003; Enwere et al., 2004; Ferron et al., 2004; Maslov et al., 2004).”

“For this purpose, we studied the effect of an intracerebroventricular infusion of FGF, a known mitotic agent in the SVZ that stimulates neurogenesis (Jin et al. 2003; Kuhn et al. 1997).”

“Luo et al , 2006 ) mediated by an age-related alteration in the cellular microenvironment (”

“As a result, FGF2 therapy has been suggested in several other diseases, including the healing and strengthening of vessel wall aneurisms (54), replacement of neurons (55), and regeneration of osteoporetic bone (56).”

“Double-immunolabeling study was conducted as previous described [19].”

“Among these genes, Egf, Fgf-2, and Vegf are well known as NSC mitogenic factors (Cheng et al. 2002; Jin et al. 2003), whereas Notch2 plays a role in a variety of developmental processes by controlling cell fate decisions (Larsson et al.”

“Aging and other conditions affect processes of neurogenesis, and this leads to impairment of cognitive function (Drapeau et al., 2003; Jin et al., 2003).”

“One reason for the decreased neurogenesis in the adult SVZ compared to the embryo is the lack of retinoids including atRA in the forebrain as neurogenesis can be increased by agonists of RARβ and α, two receptors which are known to be expressed in the adult SVZ (Haskell and LaMantia, 2005) and which can be autoregulat…”

“For instance, HB-EGF has been reported to exert protective effects in rodent models of ischemic brain injury (Jin et al., 2004) and to enhance neurogenesis in the subventricular zone and hippocamal dentate gyrus (Jin et al., 2003; Jin et al., 2004).”

“Migration of neural precursors from SVZ to the OB along the RMS is a well-established phenomenon [25–27].”

“Conversely, the infusion of FGF2 or EGF into the aged mouse brain promotes NSC proliferation [22].”

“For example, fibroblast growth factor (FGF)-2 is expressed in adult rodent SVZ and SGZ (17) and intracerebroventricular (ICV) infusions of FGF-2 upregulate dentate neurogenesis significantly in the aged brain and also increase neurogenesis in SVZ and neuronal migration to the olfactory bulb (18,19).”

“Furthermore, central administration of several of these neurotrophic factors stimulates neurogenesis in both the SVZ and dentate gyrus of aged animals (Jin et al., 2003; Hattiangady et al., 2005; Shetty et al., 2005).”

“For instance, increased neurogenesis is observed with exposure to enriched environment (Kempermann et al ., 1998, 2002; Nilsson et al ., 1999) and physical exercise (van Praag et al ., 1999, 2005), increased levels of serotonin (Gould, 1999) and NSC proliferation factors such as brain-derived neurotrophic factor (BDNF…”

“Moreover, neurogenesis declines during aging and NSC/NPC grafts were shown to improve cognitive function of aged brain (Hodges et al., 2000; Jin et al., 2003; Qu et al., 2001).”

“As a pleiotropic protein, basic fibroblast growth factor (bFGF) plays an important role in the adult neurogenesis (Gerdes et al. 1992; Jin et al. 2003; Tureyen et al. 2005; Zhao et al. 2007).”

“This might explain the partial drift in the functional features that we and others observed in long-term cultured NSCs as well as the reported ability of serially passaged NSCs to integrate and differentiate properly if placed in a homolog environment (Herrera et al., 1999; Klein et al., 2005).”

“Furthermore, exogenous bFGF can also restore neurogenesis in the hippocampus and SVZ in the aged animals (Jin et al., 2003; Rai et al., 2007).”