scholarly journals Functional rejuvenation of aged neural stem cells by Plagl2 and anti-Dyrk1a activity

2021 ◽  
Author(s):  
Takashi Kaise ◽  
Masahiro Fukui ◽  
Risa Sueda ◽  
Wenhui Piao ◽  
Mayumi Yamada ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Genetic Disorder ◽  
Chromatin Accessibility ◽  
Aged Mouse ◽  
Gene Combination ◽  
Age Related ◽  
Nuclear Factors ◽  
Adult Nscs ◽  
Senescence Associated Genes

The regenerative potential of neural stem cells (NSCs) declines during aging, leading to cognitive dysfunctions. This decline involves up-regulation of senescence-associated genes, but inactivation of such genes failed to reverse aging of hippocampal NSCs. Because many genes are up-regulated or down-regulated during aging, manipulation of single genes would be insufficient to reverse aging. Here we searched for a gene combination that can rejuvenate NSCs in the aged mouse brain from nuclear factors differentially expressed between embryonic and adult NSCs and their modulators. We found that a combination of inducing the zinc finger transcription factor gene Plagl2 and inhibiting Dyrk1a, a gene associated with Down syndrome (a genetic disorder known to accelerate aging), rejuvenated aged hippocampal NSCs, which already lost proliferative and neurogenic potential. Such rejuvenated NSCs proliferated and produced new neurons continuously at the level observed in juvenile hippocampi, leading to improved cognition. Epigenome, transcriptome, and live-imaging analyses indicated that this gene combination induces up-regulation of embryo-associated genes and down-regulation of age-associated genes by changing their chromatin accessibility, thereby rejuvenating aged dormant NSCs to function like juvenile active NSCs. Thus, aging of NSCs can be reversed to induce functional neurogenesis continuously, offering a way to treat age-related neurological disorders.

scholarly journals GDF11 induces differentiation and apoptosis and inhibits migration of C17.2 neural stem cells via modulating MAPK signaling pathway

2018 ◽  
Author(s):  
Zongkui Wang ◽  
Miaomiao Dou ◽  
Fengjuan Liu ◽  
Peng Jiang ◽  
Shengliang Ye ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Term Treatment ◽  
Population Doubling ◽  
Proteome Profiling ◽  
Positive Effects ◽  
Age Related ◽  
Long Term Treatment

GDF11, a member of TGF-β superfamily, has recently received widespread attention as a novel anti-ageing/rejuvenation factor to reverse age-related dysfunctions in heart and skeletal muscle, and to induce angiogenesis and neurogenesis. However, these positive effects of GDF11 were challenged by several other studies. Furthermore, the mechanism is still not well understood. In the present study, we evaluated the effects and underlying mechanisms of GDF11 on C17.2 neural stem cells. GDF11 induced differentiation and apoptosis, and suppressed migration of C17.2 neural stem cells. Besides, GDF11 slightly increased cell viability after 24h treatment, showed no effects on proliferation for about 10 days of cultivation, and slightly decreased cumulative population doubling for long-term treatment (p<0.05). Phospho-proteome profiling array displayed that GDF11 significantly increased the phosphorylation level of 13 serine/threonine kinases (p<0.01), including p-p38, p-ERK and p-Akt, in C17.2 cells, which implied the activation of MAPK pathway. Western blot validated that the results of phospho-proteome profiling array were reliable. Based on functional analysis, we demonstrated that the differentially expressed proteins were mainly involved in signal transduction which was implicated in cellular behavior. Collectively, our findings suggest that, for neurogenesis, GDF11 might not be the desired rejuvenation factor, but a potential target for pharmacologic blockade.

scholarly journals Transcriptional Reprogramming of Skeletal Muscle Stem Cells by the Niche Environment

2021 ◽  
Author(s):  
Felicia Lazure ◽  
Rick Farouni ◽  
Korin Sahinyan ◽  
Darren M. Blackburn ◽  
Aldo Hernandez-Corchado ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Tissue Regeneration ◽  
Adult Stem Cells ◽  
Cell Function ◽  
Chromatin Accessibility ◽  
Muscle Stem Cells ◽  
Age Related ◽  
A Genome ◽  
Skeletal Muscle Stem Cells

Adult stem cells are indispensable for tissue regeneration. Tissue-specific stem cells reside in a specialized location called their niche, where they are in constant cross talk with neighboring niche cells and circulatory signals from their environment. Aging has a detrimental effect on the number and the regenerative function of various stem cells. However, whether the loss of stem cell function is a cause or consequence of their aging niche is unclear. Using skeletal muscle stem cells (MuSCs) as a model, we decouple cell-intrinsic from niche-mediated extrinsic effects of aging on their transcriptome. By combining in vivo MuSC heterochronic transplantation models and computational methods, we show that on a genome-wide scale, age-related altered genes fall into two distinct categories regarding their response to the niche environment. Genes that are inelastic in their response to the niche exhibit altered chromatin accessibility and are associated with differentially methylated regions (DMRs) between young and aged cells. On the other hand, genes that are restorable by niche exposure exhibit altered transcriptome but show no change in chromatin accessibility or DMRs. Taken together, our data suggest that the niche environment plays a decisive role in controlling the transcriptional activity of MuSCs, and exposure to a young niche can reverse approximately half of all age-associated changes that are not epigenetically encoded. The muscle niche therefore serves as an important therapeutic venue to mitigate the negative consequence of aging on tissue regeneration.

scholarly journals Increasing neurogenesis refines hippocampal activity rejuvenating navigational learning strategies and contextual memory throughout life

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Gabriel Berdugo-Vega ◽  
Gonzalo Arias-Gil ◽  
Adrian López-Fernández ◽  
Benedetta Artegiani ◽  
Joanna M. Wasielewska ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Learning Strategies ◽  
Inhibitory Effect ◽  
Cell Cycle Regulators ◽  
Contextual Memory ◽  
Age Related ◽  
Hippocampal Activity ◽  
Navigational Learning ◽  
The Brain

AbstractFunctional plasticity of the brain decreases during ageing causing marked deficits in contextual learning, allocentric navigation and episodic memory. Adult neurogenesis is a prime example of hippocampal plasticity promoting the contextualisation of information and dramatically decreases during ageing. We found that a genetically-driven expansion of neural stem cells by overexpression of the cell cycle regulators Cdk4/cyclinD1 compensated the age-related decline in neurogenesis. This triggered an overall inhibitory effect on the trisynaptic hippocampal circuit resulting in a changed profile of CA1 sharp-wave ripples known to underlie memory consolidation. Most importantly, increased neurogenesis rescued the age-related switch from hippocampal to striatal learning strategies by rescuing allocentric navigation and contextual memory. Our study demonstrates that critical aspects of hippocampal function can be reversed in old age, or compensated throughout life, by exploiting the brain’s endogenous reserve of neural stem cells.

scholarly journals The Surface Proteome of Adult Neural Stem Cells in Zebrafish Unveils Long-Range Cell-Cell Connections and Age-Related Changes in Responsiveness to IGF

2019 ◽  
Vol 12 (2) ◽  
pp. 258-273 ◽  
Author(s):  
Jara Obermann ◽  
Felicia Wagner ◽  
Anita Kociaj ◽  
Alessandro Zambusi ◽  
Jovica Ninkovic ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Long Range ◽  
Adult Neural Stem Cells ◽  
Age Related ◽  
Range Cell ◽  
Surface Proteome ◽  
Age Related Changes ◽  
Cell Cell

scholarly journals Chromatin alterations in the aging lung change progenitor cell activity

2021 ◽  
Author(s):  
Samuel P. Rowbotham ◽  
Patrizia Pessina ◽  
Carolina Garcia de Alba Rivas ◽  
Jingyun Li ◽  
Irene Wong ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Cell Activity ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Alveolar Type ◽  
Aged Mouse ◽  
Efficient Manner ◽  
Age Related ◽  
Multipotent Progenitor Cells

The lung contains multiple progenitor cell types that respond to damage, but how their responses are choreographed and why they decline with age is poorly understood. We report that histone H3 lysine 9 di-methylation (K9me2), mediated by histone methyltransferase G9a, regulates the dynamics of lung epithelial progenitor cells, and this regulation deteriorates with age. In aged mouse lungs, K9me2 loss coincided with lower frequency and activity of alveolar type 2 (AT2) cell progenitors. In contrast, K9me2 loss resulted in increased frequency and activity of multipotent progenitor cells with bronchiolar and alveolar potential (BASCs) and bronchiolar progenitors. K9me2 depletion in young mice through deletion or inhibition of G9a decreased AT2 progenitor activity and impaired alveolar injury regeneration. Conversely, K9me2 depletion increased chromatin accessibility of bronchiolar cell genes, increased BASC frequency and accelerated bronchiolar repair. K9me2 depletion also resulted in increased bronchiolar cell expression of the SARS-CoV2 receptor Ace2 in aged lungs. These data point to K9me2 and G9a as a critical regulator of the balance of lung progenitor cell regenerative responses and prevention of susceptibility to age-related lung diseases. These findings indicate that epigenetic regulation coordinates progenitor cell populations to expedite regeneration in the most efficient manner and disruption of this regulation presents significant challenges to lung health.

scholarly journals GDF11 induces differentiation and apoptosis and inhibits migration of C17.2 neural stem cells via modulating MAPK signaling pathway

2018 ◽  
Author(s):  
Zongkui Wang ◽  
Miaomiao Dou ◽  
Fengjuan Liu ◽  
Peng Jiang ◽  
Shengliang Ye ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Term Treatment ◽  
Population Doubling ◽  
Proteome Profiling ◽  
Positive Effects ◽  
Age Related ◽  
Long Term Treatment

GDF11, a member of TGF-β superfamily, has recently received widespread attention as a novel anti-ageing/rejuvenation factor to reverse age-related dysfunctions in heart and skeletal muscle, and to induce angiogenesis and neurogenesis. However, these positive effects of GDF11 were challenged by several other studies. Furthermore, the mechanism is still not well understood. In the present study, we evaluated the effects and underlying mechanisms of GDF11 on C17.2 neural stem cells. GDF11 induced differentiation and apoptosis, and suppressed migration of C17.2 neural stem cells. Besides, GDF11 slightly increased cell viability after 24h treatment, showed no effects on proliferation for about 10 days of cultivation, and slightly decreased cumulative population doubling for long-term treatment (p<0.05). Phospho-proteome profiling array displayed that GDF11 significantly increased the phosphorylation level of 13 serine/threonine kinases (p<0.01), including p-p38, p-ERK and p-Akt, in C17.2 cells, which implied the activation of MAPK pathway. Western blot validated that the results of phospho-proteome profiling array were reliable. Based on functional analysis, we demonstrated that the differentially expressed proteins were mainly involved in signal transduction which was implicated in cellular behavior. Collectively, our findings suggest that, for neurogenesis, GDF11 might not be the desired rejuvenation factor, but a potential target for pharmacologic blockade.

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