Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain

Kalamakis, Georgios; Brune, D.; Ravichandran, Srikanth; Bolz, J.; Fan, Wenqiang; Ziebell, Frederik; Stiehl, Thomas; Catalá-Martinez, Francisco; Kupke, Janina; Zhao, Sheng; Llorens-Bobadilla, Enric; Bauer, Katharina; Limpert, Stefanie; Berger, Birgit S.; Christen, Urs; Schmezer, Peter; Mallm, Jan‐Philipp; Berninger, Benedikt; Anders, Simon; Sol, Antonio del; Marciniak–Czochra, Anna; Martín-Villalba, Ana

doi:10.1016/j.cell.2019.01.040

Cited by 303 publications

(442 citation statements)

References 58 publications

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“…Corroborating our earlier findings, a number of recent studies have highlighted the critical importance of WβC crosstalk with survival and inflammatory pathways in inciting neurogenesis and neurorepair Kalamakis et al, 2019;Kase, Otsu, Shimazaki, & Okano, 2019;Mishra et al, 2019;Morrow & Moore, 2019;Ray et al, 2018;Singh, Mishra, Bharti, et al, 2018b;Singh, Mishra, Mohanbhai, et al, 2018a;Singh, Mishra, & Shukla, 2016).…”

Section: Introductionsupporting

confidence: 85%

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

et al. 2020

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A common hallmark of age‐dependent neurodegenerative diseases is an impairment of adult neurogenesis. Wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin (WβC) signalling is a vital pathway for dopaminergic (DAergic) neurogenesis and an essential signalling system during embryonic development and aging, the most critical risk factor for Parkinson's disease (PD). To date, there is no known cause or cure for PD. Here we focus on the potential to reawaken the impaired neurogenic niches to rejuvenate and repair the aged PD brain. Specifically, we highlight WβC‐signalling in the plasticity of the subventricular zone (SVZ), the largest germinal region in the mature brain innervated by nigrostriatal DAergic terminals, and the mesencephalic aqueduct‐periventricular region (Aq‐PVR) Wnt‐sensitive niche, which is in proximity to the SNpc and harbors neural stem progenitor cells (NSCs) with DAergic potential. The hallmark of the WβC pathway is the cytosolic accumulation of β‐catenin, which enters the nucleus and associates with T cell factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors, leading to the transcription of Wnt target genes. Here, we underscore the dynamic interplay between DAergic innervation and astroglial‐derived factors regulating WβC‐dependent transcription of key genes orchestrating NSC proliferation, survival, migration and differentiation. Aging, inflammation and oxidative stress synergize with neurotoxin exposure in “turning off” the WβC neurogenic switch via down‐regulation of the nuclear factor erythroid‐2‐related factor 2/Wnt‐regulated signalosome, a key player in the maintenance of antioxidant self‐defense mechanisms and NSC homeostasis. Harnessing WβC‐signalling in the aged PD brain can thus restore neurogenesis, rejuvenate the microenvironment, and promote neurorescue and regeneration.

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Section: Introductionsupporting

confidence: 85%

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

et al. 2020

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“…EdU-Ki67+ NSCs) declined progressively and substantially with age, indicating that dormant NSCs were progressing into a deeper state of quiescence ( Figure 2B, C). This observation is consistent with the analysis of quiescence in fibroblast cultures (Kwon et al, 2017) and with recent modelling predictions and experimental data showing that NSCs in the adult ventricular-subventricular zone (V-SVZ) deepen their quiescence with age (Bast et al, 2018;Kalamakis et al, 2019;.…”

Section: Active Nscs Progressively Acquire the Capacity To Return To supporting

confidence: 90%

“…The probability a is referred to as self-renewal probability or fraction of self-renewal [3,5,6]. • In agreement with our previous work and with experimental data [2] we assume that NSC originating from division become quiescent.…”

Section: Statisticssupporting

confidence: 77%

“…Interestingly, the increased quiescence of NSCs in the V-SVZ niche was found to occur as early as 7-months of age and to be mediated through changes in inflammatory signalling. It was suggested that this early change might not reflect stem cell dysfunction but help preserve the NSC pool (Kalamakis et al, 2019). Our transcriptional analysis of NSCs in 1-month-old and 6-monthold mice shows little change over time in inflammatory, mitochondrial and lysosomal pathways that typify stem cell aging (Table S4) (Leeman et al, 2018).…”

Section: Discussionmentioning

confidence: 88%

“…The model is summarized in Figure 1. It is an extension of previous models [2,7,8]. The new aspect of the model introduced here is the distinction between resting and dormant NSC.…”

Section: Statisticsmentioning

confidence: 97%

See 2 more Smart Citations

Progressive changes in hippocampal stem cell properties ensure lifelong neurogenesis

Harris

Rigo

Stiehl

et al. 2020

Preprint

Self Cite

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Neural stem cell numbers fall rapidly in the hippocampus of juvenile mice but stabilise during adulthood, ensuring lifelong hippocampal neurogenesis. We show that this reduction in stem cell depletion rate is the result of multiple coordinated changes in stem cell behaviour. In particular, while active neural stem cells divide only once or twice before differentiating rapidly in juveniles, they increasingly return to a resting state of shallow quiescence and progress through additional self-renewing divisions in adulthood. Single-cell transcriptomic, mathematical modelling and label-retention analyses indicate that resting cells have a higher activation rate and greater contribution to neurogenesis than dormant cells, which have not left quiescence. These progressive changes in stem cell behaviour result from reduced expression of the pro-activation protein ASCL1 due to increased post-translational degradation. These mechanisms help reconcile current contradictory models of hippocampal NSC dynamics and may contribute to the different rates of decline of hippocampal neurogenesis in mammalian species including humans.

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Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan

Matteini,

Montserrat‐Vazquez,

Florian

2024

FEBS Letters

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Aging is associated with a global decline in stem cell function. To date, several strategies have been proposed to rejuvenate aged stem cells: most of these result in functional improvement of the tissue where the stem cells reside, but the impact on the lifespan of the whole organism has been less clearly established. Here, we review some of the most recent work dealing with interventions that improve the regenerative capacity of aged somatic stem cells in mammals and that might have important translational possibilities. Overall, we underscore that somatic stem cell rejuvenation represents a strategy to improve tissue homeostasis upon aging and present some recent approaches with the potential to affect health span and lifespan of the whole organism.

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Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain

Cited by 303 publications

References 58 publications

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

Progressive changes in hippocampal stem cell properties ensure lifelong neurogenesis

Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan

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