scholarly journals Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in muscle stem cells

2018 ◽  
Author(s):  
Irene Hernando-Herraez ◽  
Brendan Evano ◽  
Thomas Stubbs ◽  
Pierre-Henri Commere ◽  
Stephen Clark ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Stem Cell ◽  
Functional Decline ◽  
Cell Number ◽  
Transcriptional Networks ◽  
Mouse Muscle ◽  
Muscle Stem Cells ◽  
Age Related ◽  
Cell To Cell Variability

Age-related tissue alterations have been associated with a decline in stem cell number and function. Although increased cell-to-cell variability in transcription or epigenetic marks has been proposed to be a major hallmark of ageing, little is known about the molecular diversity of stem cells during ageing. Here, by combined single-cell transcriptome and DNA methylome profiling in mouse muscle stem cells, we show a striking global increase of uncoordinated transcriptional heterogeneity together with context-dependent alterations of DNA methylation with age. Importantly, promoters with increased methylation heterogeneity are associated with increased transcriptional heterogeneity of the genes they drive. Notably, old cells that change the most with age reveal alterations in the transcription of genes regulating cell-niche interactions. These results indicate that epigenetic drift, by accumulation of stochastic DNA methylation changes in promoters, is a substantial driver of the degradation of coherent transcriptional networks with consequent stem cell functional decline during ageing.

scholarly journals Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Irene Hernando-Herraez ◽  
Brendan Evano ◽  
Thomas Stubbs ◽  
Pierre-Henri Commere ◽  
Marc Jan Bonder ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Stem Cell ◽  
Single Cell ◽  
Cell Number ◽  
Transcriptional Networks ◽  
Mouse Muscle ◽  
Muscle Stem Cells ◽  
Age Related ◽  
Cell To Cell Variability

Abstract Age-related tissue alterations have been associated with a decline in stem cell number and function. Although increased cell-to-cell variability in transcription or epigenetic marks has been proposed to be a major hallmark of ageing, little is known about the molecular diversity of stem cells during ageing. Here we present a single cell multi-omics study of mouse muscle stem cells, combining single-cell transcriptome and DNA methylome profiling. Aged cells show a global increase of uncoordinated transcriptional heterogeneity biased towards genes regulating cell-niche interactions. We find context-dependent alterations of DNA methylation in aged stem cells. Importantly, promoters with increased methylation heterogeneity are associated with increased transcriptional heterogeneity of the genes they drive. These results indicate that epigenetic drift, by accumulation of stochastic DNA methylation changes in promoters, is associated with the degradation of coherent transcriptional networks during stem cell ageing. Furthermore, our observations also shed light on the mechanisms underlying the DNA methylation clock.

scholarly journals Age-Related Changes in Methylome and Transcriptome of Hematopotietic Stem Cells Underlie Natural Genetic Variations

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2660-2660
Author(s):  
Ying Liang
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Stem Cell ◽  
Aging Process ◽  
Expression Patterns ◽  
Genetic Variations ◽  
Cell Aging ◽  
Hematopoietic Stem ◽  
Age Related ◽  
Age Related Changes

The aging of hematopoietic stem cells (HSCs) contributes to the aging of blood system and perhaps the whole organism. The aging process is coordinately determined by both genetic and epigenetic factors, and demonstrates inter-individual variations. We used high-throughput sequencing methods to study the age-dependent changes of genome-wide DNA methylation and gene expression patterns in HSCs of C57BL/6 (B6) and DBA/2 mouse strains, which have shown natural variations in HSC aging process. We observed global age-associated decrease of DNA methylation in both strains, but D2 HSCs have a stronger loss of epigenetic control than B6 stem cells during aging. Majority age-related changes of DNA methylation occur from young to mid-aged stages. We identified stable strain-specific differentially methylated regions (DMRs) that overlap with cis-eQTLs. Moreover, transcription factor binding site motifs are more likely to be disrupted in the DMRs, suggesting the potential impact of genetic variations on epigenetic regulation of HSC aging. We further demonstrated that strain-specific DMRs have more profound effects on the aging of B6 HSCs than D2 stem cells. Transposons are differentially regulated by the DMRs in the two strains, in which D2 HSCs are prone to transposon insertion. This study comprehensively investigated the effects of natural genetic and epigenetic variations on HSC aging. Loss of DNA methylation is an epigenetic signature of stem cell aging, and DNA methylation variations correlates with genetic variations, both contributing to inter-individual differences in stem cell and perhaps organismal aging. Disclosures No relevant conflicts of interest to declare.

scholarly journals DNA Methylation in Skeletal Muscle Stem Cell Specification, Proliferation, and Differentiation

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Rhianna C. Laker ◽  
James G. Ryall
Keyword(s):  
Skeletal Muscle ◽  
Dna Methylation ◽  
Stem Cells ◽  
Stem Cell ◽  
Muscle Development ◽  
Epigenetic Modification ◽  
Later Life ◽  
Muscle Stem Cell ◽  
Adult Skeletal Muscle ◽  
Muscle Stem Cells

An unresolved and critically important question in skeletal muscle biology is how muscle stem cells initiate and regulate the genetic program during muscle development. Epigenetic dynamics are essential for cellular development and organogenesis in early life and it is becoming increasingly clear that epigenetic remodeling may also be responsible for the cellular adaptations that occur in later life. DNA methylation of cytosine bases within CpG dinucleotide pairs is an important epigenetic modification that reduces gene expression when located within a promoter or enhancer region. Recent advances in the field suggest that epigenetic regulation is essential for skeletal muscle stem cell identity and subsequent cell development. This review summarizes what is currently known about how skeletal muscle stem cells regulate the myogenic program through DNA methylation, discusses a novel role for metabolism in this process, and addresses DNA methylation dynamics in adult skeletal muscle in response to physical activity.

scholarly journals Autophagy as a Therapeutic Target to Enhance Aged Muscle Regeneration

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 183 ◽  
Author(s):  
David Lee ◽  
Akshay Bareja ◽  
David Bartlett ◽  
James White
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Muscle Regeneration ◽  
Immune Cell ◽  
Regenerative Capacity ◽  
Adult Skeletal Muscle ◽  
Muscle Stem Cells ◽  
Age Related ◽  
Skeletal Muscle Stem Cells

Skeletal muscle has remarkable regenerative capacity, relying on precise coordination between resident muscle stem cells (satellite cells) and the immune system. The age-related decline in skeletal muscle regenerative capacity contributes to the onset of sarcopenia, prolonged hospitalization, and loss of autonomy. Although several age-sensitive pathways have been identified, further investigation is needed to define targets of cellular dysfunction. Autophagy, a process of cellular catabolism, is emerging as a key regulator of muscle regeneration affecting stem cell, immune cell, and myofiber function. Muscle stem cell senescence is associated with a suppression of autophagy during key phases of the regenerative program. Macrophages, a key immune cell involved in muscle repair, also rely on autophagy to aid in tissue repair. This review will focus on the role of autophagy in various aspects of the regenerative program, including adult skeletal muscle stem cells, monocytes/macrophages, and corresponding age-associated dysfunction. Furthermore, we will highlight rejuvenation strategies that alter autophagy to improve muscle regenerative function.

scholarly journals Transcriptional reprogramming of skeletal muscle stem cells by the niche environment

2021 ◽  
Author(s):  
Vahab Soleimani ◽  
Felicia Lazure ◽  
Rick Farouni ◽  
Korin Sahinyan ◽  
Darren Blackburn ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Tissue Regeneration ◽  
Adult Stem Cells ◽  
Cell Function ◽  
Critical Role ◽  
Negative Consequences ◽  
Muscle Stem Cells ◽  
Age Related

Abstract Adult stem cells are indispensable for tissue regeneration, but the number and regenerative capacity of stem cells declines with age. Whether the decrease in stem cell function is the cause or consequence of the aging of a tissue is unclear. Evidence suggests that the niche environment plays a critical role in the regulation of adult stem cell function6-10. However, quantification of the niche effect on stem cell function is an unmet challenge. Using muscle stem cells (MuSCs) as a model, we show that aging leads to a significant transcriptomic shift in MuSC subpopulations. By combining in vivo MuSC transplantation, multi-omics and computational methods, we show that the expression of approximately half of all age-altered genes in MuSCs can be restored by exposure to a young niche environment. Age-related genes whose expression is not restored exhibit altered chromatin accessibility and are associated with differentially methylated regions between young and aged cells. Our findings establish that the expression of the majority of age-related altered genes that are not epigenetically encoded is readily restorable by exposure to a young niche environment. The stem cell niche may therefore be an important therapeutic target to mitigate the negative consequences of aging on tissue regeneration.

scholarly journals Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Wenxuan Liu ◽  
Alanna Klose ◽  
Sophie Forman ◽  
Nicole D Paris ◽  
Lan Wei-LaPierre ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Neuromuscular Junction ◽  
Neuromuscular Junctions ◽  
Aged Mouse ◽  
Muscle Stem Cell ◽  
Adult Skeletal Muscle ◽  
Muscle Stem Cells ◽  
Age Related

Neuromuscular junction degeneration is a prominent aspect of sarcopenia, the age-associated loss of skeletal muscle integrity. Previously, we showed that muscle stem cells activate and contribute to mouse neuromuscular junction regeneration in response to denervation (Liu et al., 2015). Here, we examined gene expression profiles and neuromuscular junction integrity in aged mouse muscles, and unexpectedly found limited denervation despite a high level of degenerated neuromuscular junctions. Instead, degenerated neuromuscular junctions were associated with reduced contribution from muscle stem cells. Indeed, muscle stem cell depletion was sufficient to induce neuromuscular junction degeneration at a younger age. Conversely, prevention of muscle stem cell and derived myonuclei loss was associated with attenuation of age-related neuromuscular junction degeneration, muscle atrophy, and the promotion of aged muscle force generation. Our observations demonstrate that deficiencies in muscle stem cell fate and post-synaptic myogenesis provide a cellular basis for age-related neuromuscular junction degeneration and associated skeletal muscle decline.

scholarly journals Pink1 and Parkin regulate Drosophila intestinal stem cell proliferation during stress and aging

2017 ◽  
Vol 216 (8) ◽  
pp. 2315-2327 ◽  
Author(s):  
Christopher L. Koehler ◽  
Guy A. Perkins ◽  
Mark H. Ellisman ◽  
D. Leanne Jones
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mitochondrial Dynamics ◽  
Cell Metabolism ◽  
Functional Decline ◽  
Cell Activity ◽  
Cellular Tissue ◽  
Tissue Homeostasis ◽  
Age Related

Intestinal stem cells (ISCs) maintain the midgut epithelium in Drosophila melanogaster. Proper cellular turnover and tissue function rely on tightly regulated rates of ISC division and appropriate differentiation of daughter cells. However, aging and epithelial injury cause elevated ISC proliferation and decreased capacity for terminal differentiation of daughter enteroblasts (EBs). The mechanisms causing functional decline of stem cells with age remain elusive; however, recent findings suggest that stem cell metabolism plays an important role in the regulation of stem cell activity. Here, we investigate how alterations in mitochondrial homeostasis modulate stem cell behavior in vivo via RNA interference–mediated knockdown of factors involved in mitochondrial dynamics. ISC/EB-specific knockdown of the mitophagy-related genes Pink1 or Parkin suppresses the age-related loss of tissue homeostasis, despite dramatic changes in mitochondrial ultrastructure and mitochondrial damage in ISCs/EBs. Maintenance of tissue homeostasis upon reduction of Pink1 or Parkin appears to result from reduction of age- and stress-induced ISC proliferation, in part, through induction of ISC senescence. Our results indicate an uncoupling of cellular, tissue, and organismal aging through inhibition of ISC proliferation and provide insight into strategies used by stem cells to maintain tissue homeostasis despite severe damage to organelles.

Stem Cell Function, Self-Renewal, Heterogeneity, and Regenerative Potential in Skeletal Muscle Stem Cells

2012 ◽  
Vol 2 (1) ◽  
pp. 11-21
Author(s):  
Silvia Cristini ◽  
Giulio Alessandri ◽  
Francesco Acerbi ◽  
Daniela Tavian ◽  
Eugenio A. Parati ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Function ◽  
Self Renewal ◽  
Muscle Stem Cells ◽  
Skeletal Muscle Stem Cells

Stem Cell Function, Self-Renewal, Heterogeneity, and Regenerative Potential in Skeletal Muscle Stem Cells

2012 ◽  
Vol 2 (1) ◽  
pp. 11-21
Author(s):  
Silvia Cristini ◽  
Giulio Alessandri ◽  
Francesco Acerbi ◽  
Daniela Tavian ◽  
Eugenio A. Parati ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Function ◽  
Self Renewal ◽  
Muscle Stem Cells ◽  
Skeletal Muscle Stem Cells

scholarly journals Empowering Muscle Stem Cells for the Treatment of Duchenne Muscular Dystrophy

2021 ◽  
pp. 1-14
Author(s):  
Romina L. Filippelli ◽  
Natasha C. Chang
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Cell Function ◽  
Critical Role ◽  
Membrane Integrity ◽  
Muscle Membrane ◽  
Muscle Stem Cell ◽  
Muscle Stem Cells

Duchenne muscular dystrophy (DMD) is a devastating and debilitating muscle degenerative disease affecting 1 in every 3,500 male births worldwide. DMD is progressive and fatal; accumulated weakening of the muscle tissue leads to an inability to walk and eventual loss of life due to respiratory and cardiac failure. Importantly, there remains no effective cure for DMD. DMD is caused by defective expression of the <i>DMD</i> gene, which encodes for dystrophin, a component of the dystrophin glycoprotein complex. In muscle fibers, this protein complex plays a critical role in maintaining muscle membrane integrity. Emerging studies have shown that muscle stem cells, which are adult stem cells responsible for muscle repair, are also affected in DMD. DMD muscle stem cells do not function as healthy muscle stem cells, and their impairment contributes to disease progression. Deficiencies in muscle stem cell function include impaired establishment of cell polarity leading to defective asymmetric stem cell division, reduced myogenic commitment, impaired differentiation, altered metabolism, and enhanced entry into senescence. Altogether, these findings indicate that DMD muscle stem cells are dysfunctional and have impaired regenerative potential. Although recent advances in adeno-associated vector and antisense oligonucleotide-mediated mechanisms for gene therapy have shown clinical promise, the current therapeutic strategies for muscular dystrophy do not effectively target muscle stem cells and do not address the deficiencies in muscle stem cell function. Here, we discuss the merits of restoring endogenous muscle stem cell function in degenerating muscle as a viable regenerative medicine strategy to mitigate DMD.

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