Regenerative Capacity of Old Muscle Stem Cells Declines without Significant Accumulation of DNA Damage

BACKGROUND: There is probably no single way to age. Indeed, so far there is no single accepted explanation or mechanisms of aging (although more than 300 theories have been proposed). There is an overall decline in tissue regenerative potential with age, and the question arises as to whether this is due to the intrinsic aging of stem cells or rather to the impairment of stem cell function in the aged tissue environment.CONTENT: Recent data suggest that we age, in part, because our self-renewing stem cells grow old as a result of heritable intrinsic events, such as DNA damage, as well as extrinsic forces, such as changes in their supporting niches. Mechanisms that suppress the development of cancer, such as senescence and apoptosis, which rely on telomere shortening and the activities of p53 and p16INK4a may also induce an unwanted consequence: a decline in the replicative function of certain stem cells types with advancing age. This decrease regenerative capacity appears to pointing to the stem cell hypothesis of aging.SUMMARY: Recent evidence suggested that we grow old partly because of our stem cells grow old as a result of mechanisms that suppress the development of cancer over a lifetime. We believe that a further, more precise mechanistic understanding of this process will be required before this knowledge can be translated into human anti-aging therapies.KEYWORDS: stem cells, senescence, telomere, DNA damage, epigenetic, aging

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Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation

10.1101/2020.05.20.107219 ◽

2020 ◽

Author(s):

Brendan Evano ◽

Diljeet Gill ◽

Irene Hernando-Herraez ◽

Glenda Comai ◽

Thomas M. Stubbs ◽

...

Keyword(s):

Stem Cells ◽

Skeletal Muscles ◽

Molecular Diversity ◽

Anatomical Location ◽

Limb Muscle ◽

Regenerative Capacity ◽

Self Renewal ◽

Site Specific ◽

Muscle Stem Cells ◽

Molecular Determinants

ABSTRACTAdult skeletal muscles are maintained during homeostasis and regenerated upon injury by muscle stem cells (MuSCs). A heterogeneity in self-renewal, differentiation and regeneration properties has been reported for MuSCs based on their anatomical location. Although MuSCs derived from extraocular muscles (EOM) have a higher regenerative capacity than those derived from limb muscles, the molecular determinants that govern these differences remain undefined. Here we show that EOM and limb MuSCs have distinct DNA methylation signatures associated with enhancers of location-specific genes, and that the EOM transcriptome is reprogrammed following transplantation into a limb muscle environment. Notably, EOM MuSCs expressed host-site specific positional Hox codes after engraftment and self-renewal within the host muscle. However, about 10% of EOM-specific genes showed engraftment-resistant expression, pointing to cell-intrinsic molecular determinants of the higher engraftment potential of EOM MuSCs. Our results underscore the molecular diversity of distinct MuSC populations and molecularly define their plasticity in response to microenvironmental cues. These findings provide insights into strategies designed to improve the functional capacity of MuSCs in the context of regenerative medicine.

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Skeletal Muscle Stem Cells from PSC-Derived Teratomas Have Functional Regenerative Capacity

Cell Stem Cell ◽

10.1016/j.stem.2018.06.010 ◽

2018 ◽

Vol 23 (1) ◽

pp. 74-85.e6 ◽

Cited By ~ 19

Author(s):

Sunny Sun-Kin Chan ◽

Robert W. Arpke ◽

Antonio Filareto ◽

Ning Xie ◽

Matthew P. Pappas ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Regenerative Capacity ◽

Muscle Stem Cells ◽

Skeletal Muscle Stem Cells

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Autophagy as a Therapeutic Target to Enhance Aged Muscle Regeneration

Cells ◽

10.3390/cells8020183 ◽

2019 ◽

Vol 8 (2) ◽

pp. 183 ◽

Cited By ~ 14

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.

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The effect of the muscle environment on the regenerative capacity of human skeletal muscle stem cells

Skeletal Muscle ◽

10.1186/s13395-015-0036-8 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 26

Author(s):

Jinhong Meng ◽

Maximilien Bencze ◽

Rowan Asfahani ◽

Francesco Muntoni ◽

Jennifer E Morgan

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Human Skeletal Muscle ◽

Regenerative Capacity ◽

Muscle Stem Cells ◽

Skeletal Muscle Stem Cells

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Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity

Nature Communications ◽

10.1038/ncomms1890 ◽

2012 ◽

Vol 3 (1) ◽

Cited By ~ 70

Author(s):

Mathilde Latil ◽

Pierre Rocheteau ◽

Laurent Châtre ◽

Serena Sanulli ◽

Sylvie Mémet ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Post Mortem ◽

Dormant Cell ◽

Regenerative Capacity ◽

Muscle Stem Cells ◽

Cell State ◽

Skeletal Muscle Stem Cells

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Ciliation of muscle stem cells is critical to maintain regenerative capacity and is lost during aging

10.1101/2020.03.20.000943 ◽

2020 ◽

Author(s):

A.R. Palla ◽

K.I. Hilgendorf ◽

A.V. Yang ◽

J.P. Kerr ◽

A.C. Hinken ◽

...

Keyword(s):

Stem Cells ◽

Small Molecule ◽

Hedgehog Signaling ◽

Intrinsic Defect ◽

Post Injury ◽

Regenerative Capacity ◽

Muscle Stem Cells ◽

Library Screen

AbstractDuring aging, the regenerative capacity of muscle stem cells (MuSCs) decreases, diminishing the ability of muscle to repair following injury. We performed a small molecule library screen and discovered that the proliferation and expansion of aged MuSCs is regulated by signal transduction pathways organized by the primary cilium, a cellular protrusion that serves as a sensitive sensory organelle. Abolishing MuSC cilia in vivo severely impaired injury-induced muscle regeneration. In aged muscle, a cell intrinsic defect in MuSC ciliation leading to impaired Hedgehog signaling was associated with the decrease in regenerative capacity. This deficit could be overcome by exogenous activation of Hedgehog signaling which promoted MuSC expansion, both in vitro and in vivo. Delivery of the small molecule Smoothened agonist (SAG) to muscles of aged mice restored regenerative capacity leading to increased strength post-injury. These findings provide fresh insights into the signaling dysfunction in aging and identify the ciliary Hedgehog signaling pathway as a potential therapeutic target to counter the loss of muscle regenerative capacity which accompanies aging.

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Role of satellite cells in growth and regeneration of skeletal muscles

Medycyna Weterynaryjna ◽

10.21521/mw.6349 ◽

2019 ◽

Vol 75 (11) ◽

pp. 6349-2019 ◽

Cited By ~ 1

Author(s):

ANNA CIECIERSKA ◽

TOMASZ SADKOWSKI ◽

TOMASZ MOTYL

Keyword(s):

Stem Cells ◽

Satellite Cells ◽

Skeletal Muscles ◽

Postnatal Growth ◽

Regeneration Capacity ◽

Regenerative Capacity ◽

Self Renewal ◽

Muscle Stem Cells ◽

Cell Pool

Postnatal growth and regeneration capacity of skeletal muscles is dependent mainly on adult muscle stem cells called satellite cells. Satellite cells are quiescent mononucleated cells that are normally located outside the sarcolemma within the basal lamina of the muscle fiber. Their activation, which results from injury, is manifested by mobilization, proliferation, differentiation and, ultimately, fusion into new muscle fibers. The satellite cell pool is responsible for the remarkable regenerative capacity of skeletal muscles. Moreover, these cells are capable of self-renewal and can give rise to myogenic progeny.

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