The proliferation of amplifying neural progenitor cells is impaired in the aging brain and restored by the mTOR pathway activation

Romine, Jennifer; Gao, Xiang; Xu, Xiao–Ming; So, Kwok-Fai; Chen, Jinhui

doi:10.1016/j.neurobiolaging.2015.01.003

Cited by 55 publications

(52 citation statements)

References 56 publications

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“…In fact, mTOR has been shown to regulated stem cells functions. Furthermore, activating mTOR signaling has been shown to contribute to proliferation of neural progenitor cells and enhance neurogenesis in aging mice . In undifferentiated embryonic stem cells, p70S6k activity is maintained at low levels.…”

Section: Discussionmentioning

confidence: 99%

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia

Zhang

Liu

et al. 2019

Stem Cells

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Dysfunction of neural stem cells (NSCs) has been linked to fetal neuropathy, one of the most devastating complications of gestational diabetes. Several studies have demonstrated that melatonin (Mel) exerted neuroprotective actions in various stresses. However, the role of autophagy and the involvement of Mel in NSCs in hyperglycemia (HG) have not yet been fully established. Here, we found that HG increased autophagy and autophagic flux of NSCs as evidenced by increasing LC3B II/I ratio, Beclin-1 expression, and autophagosomes. Moreover, Mel enhanced NSCs proliferation and self-renewal in HG with decreasing autophagy and activated mTOR signaling. Consistently, inhibition of autophagy by 3-Methyladenine (3-Ma) could assist Mel effects above, and induction of autophagy by Rapamycin (Rapa) could diminish Mel effects. Remarkably, HG induced premature differentiation of NSCs into neurons (Map2 positive cells) and astrocytes (GFAP positive cells). Furthermore, Mel diminished HG-induced premature differentiation and assisted NSCs in HG differentiation as that in normal condition. Coincidentally, inhibiting of NSCs autophagy by 3-Ma assisted Mel to modulate differentiation. However, increasing NSCs autophagy by Rapa disturbed the Mel effects and retarded NSCs differentiation. These findings suggested that Mel supplementation could contribute to mimicking normal NSCs proliferation and differentiation in fetal central nervous system by inhibiting autophagy in the context of gestational diabetes. STEM CELLS 2019;37:504-515 SIGNIFICANCE STATEMENTNeural stem cells play important roles in fetal neurodevelopment. The incidences of gestational diabetes are rising in the world and prevention of fetal neuropathy in gestational diabetes mellitus (GDM) needs to be deeply explored. In addition, autophagy of NSCs in HG is still unclear. Here, it is reported that HG inhibits proliferation and induces premature differentiation of NSCs by promoting autophagy and autophagic flux. The naturally occurring hormone melatonin (Mel) antagonized HG-mediated effects and maintained normal proliferation and differentiation in NSCs by modulating autophagy, which protected NSCs mainly by downregulating Beclin-1 and up modulating mTORC1 signaling. This work indicates that Mel could be used as a potential drug to aid in fetal central nervous system (CNS) development in GDM patients.

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Section: Discussionmentioning

confidence: 99%

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia

Zhang

Liu

et al. 2019

Stem Cells

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“…However, the molecular mechanism underlying the phenomenon remains elusive, impeding development of interventions aimed at promoting neurogenesis by further enhancing NSC proliferation after trauma. The mTOR signaling pathway, especially mTORC1, is known to be involved in NSC activity regulation in embryonic (Magri et al, 2011), neonatal (Hartman et al, 2013), adult (Paliouras et al, 2012), and aging (Paliouras et al, 2012; Romine et al, 2015) rodents, and its activation has also been reported after TBI in the hippocampus (Chen et al, 2007; Park et al, 2012), so we proposed that mTORC1 signaling mediates TBI-enhanced NSC proliferation.…”

Section: Resultsmentioning

confidence: 97%

“…In postnatal development, mTORC1 activity is also required for NSCs, especially in maintenance of the transit amplifying neural progenitor pool (Paliouras et al, 2012). Decline of NSC proliferation in aging rodents can also be restored by activating mTORC1 activity (Romine et al, 2015). Collectively, mTORC1 plays significant roles in regulating NSC activity, particularly in regulating NSC proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…It is required for maintaining the neural progenitor pool in adult and aging rodents (Paliouras et al, 2012). Additionally, activation of mTORC1 in aging mice rescued the decline of NSC proliferation and neurogenesis in the hippocampus (Romine et al, 2015). Sustained activation of mTORC1 in embryonic and neonatal NSCs leads to an imbalance of proliferation and differentiation (Magri et al, 2011; Hartman et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Traumatic Brain Injury Stimulates Neural Stem Cell Proliferation via Mammalian Target of Rapamycin Signaling Pathway Activation

Wang

Seekaew

Gao

et al. 2016

eNeuro

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Neural stem cells in the adult brain possess the ability to remain quiescent until needed in tissue homeostasis or repair. It was previously shown that traumatic brain injury (TBI) stimulated neural stem cell (NSC) proliferation in the adult hippocampus, indicating an innate repair mechanism, but it is unknown how TBI promotes NSC proliferation. In the present study, we observed dramatic activation of mammalian target of rapamycin complex 1 (mTORC1) in the hippocampus of mice with TBI from controlled cortical impact (CCI). The peak of mTORC1 activation in the hippocampal subgranular zone, where NSCs reside, is 24–48 h after trauma, correlating with the peak of TBI-enhanced NSC proliferation. By use of a Nestin-GFP transgenic mouse, in which GFP is ectopically expressed in the NSCs, we found that TBI activated mTORC1 in NSCs. With 5-bromo-2′-deoxyuridine labeling, we observed that TBI increased mTORC1 activation in proliferating NSCs. Furthermore, administration of rapamycin abolished TBI-promoted NSC proliferation. Taken together, these data indicate that mTORC1 activation is required for NSC proliferation postinjury, and thus might serve as a therapeutic target for interventions to augment neurogenesis for brain repair after TBI.

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“…During mammalian development, mTOR activity is required for embryonic stem cell (ESC) self-renew and differentiation (Bulut-Karslioglu et al, 2016;Cherepkova, Sineva, & Pospelov, 2016;Gomez-Salinero et al, 2016). In the nervous system, mTOR is necessary for the maintenance, proliferation, and differentiation of neural stem cell and neural progenitor cell (Lee, Lim, Park, Park, & Koh, 2016;Li et al, 2017;Romine, Gao, Xu, So, & Chen, 2015;Yang et al, 2015). mTOR signaling plays an important role during vertebrate retinal development.…”

Section: Introductionmentioning

confidence: 99%

Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

Zhang

Hou

et al. 2019

Glia

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Upon retina injury, Müller glia in the zebrafish retina respond by generating multipotent progenitors to repair the retina. However, the complete mechanisms underlying retina regeneration remain elusive. Here we report inflammation‐induced mammalian target of rapamycin (mTOR) signaling in the Müller glia is essential for retina regeneration in adult zebrafish. We show after a stab injury, mTOR is rapidly activated in Müller glia and later Müller glia‐derived progenitor cells (MGPCs). Importantly, mTOR is required for Müller glia dedifferentiation, as well as the proliferation of Müller glia and MGPCs. Interestingly, transient mTOR inhibition by rapamycin only reversibly suppresses MGPC proliferation, while its longer suppression by knocking down Raptor significantly inhibits the regeneration of retinal neurons. We further show mTOR promotes retina regeneration by regulating the mRNA expression of key reprogramming factors ascl1a and lin‐28a, cell cycle‐related genes and critical cytokines. Surprisingly, we identify microglia/macrophage‐mediated inflammation as an important upstream regulator of mTOR in the Müller glia and it promotes retina regeneration through mTOR. Our study not only demonstrates the important functions of mTOR but also reveals an interesting link between inflammation and the mTOR signaling during retina regeneration.

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The proliferation of amplifying neural progenitor cells is impaired in the aging brain and restored by the mTOR pathway activation

Cited by 55 publications

References 56 publications

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia

Traumatic Brain Injury Stimulates Neural Stem Cell Proliferation via Mammalian Target of Rapamycin Signaling Pathway Activation

Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

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