scholarly journals Skeletal muscle stem cell self-renewal and differentiation kinetics revealed by EdU lineage tracing during regeneration

2019 ◽  
Author(s):  
Bradley Pawlikowski ◽  
Nicole Dalla Betta ◽  
Tiffany Antwine ◽  
Bradley B. Olwin
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Young Adult ◽  
Muscle Injury ◽  
Lineage Tracing ◽  
Stem Cell Population ◽  
Post Injury ◽  
Self Renewal ◽  
Muscle Stem Cell

SummarySkeletal muscle maintenance and repair is dependent on the resident adult muscle stem cell (MuSC). During injury, and in diseased muscle, stem cells are engaged to replace or repair damaged muscle, which requires the stem cells to exit quiescence and expand, followed by differentiation to regenerate myofibers and self-renewal to replenish the stem cell population. Following an injury, little is known regarding the timing of MuSC (skeletal muscle stem cell) self-renewal, myoblast expansion or myoblast differentiation. To determine the timing and kinetics of these cell fate decisions, we employed DNA-based lineage tracing to label newly replicated cells and followed cell fates during skeletal muscle regeneration. MuSCs activate and expand as myoblasts rapidly following injury, where the majority differentiate into myonuclei, establishing the centrally located myonuclear pool. Re-establishing the majority MuSC pool by self-renewal occurs after 5 days post-muscle injury, accompanied by low levels of myonuclear accretion that generate only peripheral myonuclei. In aged mice, possessing ∼1/2 the number of MuSCs present in young adult mice, the timing of post injury MuSC self-renewal is delayed, and although MuSCs expansion as myoblasts in aged muscle is impaired, the number of MuSC unexpectedly recovers to young adult levels during regeneration. Following an induced muscle injury, we found that myonuclei are generated within the first four days post injury derived from myoblasts expanding from activated MuSCs. Only later during regeneration, from 5 d to 14 d post injury, is the MuSC pool replenished by self-renewal, accompanied by generation of peripheral myonuclei.

scholarly journals Dynamic heterogeneity as a strategy of stem cell self-renewal

2016 ◽  
Vol 113 (27) ◽  
pp. 7509-7514 ◽  
Author(s):  
Philip Greulich ◽  
Benjamin D. Simons
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Lineage Tracing ◽  
Stem Cell Population ◽  
Dynamic Heterogeneity ◽  
Self Renewal ◽  
Proliferation And Differentiation ◽  
Epithelial Layers ◽  
Viable Mechanism ◽  
Reversible Transfer

To maintain cycling adult tissue in homeostasis the balance between proliferation and differentiation of stem cells needs to be precisely regulated. To investigate how stem cells achieve perfect self-renewal, emphasis has been placed on models in which stem cells progress sequentially through a one-way proliferative hierarchy. However, investigations of tissue regeneration have revealed a surprising degree of flexibility, with cells normally committed to differentiation able to recover stem cell competence following injury. Here, we investigate whether the reversible transfer of cells between states poised for proliferation or differentiation may provide a viable mechanism for a heterogeneous stem cell population to maintain homeostasis even under normal physiological conditions. By addressing the clonal dynamics, we show that such models of “dynamic heterogeneity” may be equally capable of describing the results of recent lineage tracing assays involving epithelial tissues. Moreover, together with competition for limited niche access, such models may provide a mechanism to render tissue homeostasis robust. In particular, in 2D epithelial layers, we show that the mechanism of dynamic heterogeneity avoids some pathological dependencies that undermine models based on a hierarchical stem/progenitor organization.

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 Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy

2018 ◽  
Vol 115 (4) ◽  
pp. E610-E619 ◽  
Author(s):  
Onur Basak ◽  
Teresa G. Krieger ◽  
Mauro J. Muraro ◽  
Kay Wiebrands ◽  
Daniel E. Stange ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Number ◽  
Lineage Tracing ◽  
Rapid Expansion ◽  
Molecular Signature ◽  
Genetic Lineage ◽  
Proliferating Cells ◽  
Self Renewal ◽  
Genetic Lineage Tracing

The adult mouse subependymal zone provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential, and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem-cell number before some return to quiescence. This behavior is best explained by stochastic fate decisions, where stem-cell number within a shared niche fluctuates over time. Fate mapping proliferating cells using a Ki67iresCreER allele confirms that active NSCs reversibly return to quiescence, achieving long-term self-renewal. Our findings suggest a niche-based mechanism for the regulation of NSC fate and number.

scholarly journals The p38 MAPK family, a pushmi-pullyu of skeletal muscle differentiation

2009 ◽  
Vol 187 (7) ◽  
pp. 941-943 ◽  
Author(s):  
Andrew B. Lassar
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Stem Cell ◽  
Muscle Differentiation ◽  
Mitogen Activated Protein Kinase ◽  
Stem Cell Population ◽  
Skeletal Muscle Differentiation ◽  
Gene Encoding ◽  
Muscle Stem Cell ◽  
Mitogen Activated Protein

In this issue, Gillespie et al. (Gillespie et al. 2009. J. Cell Biol. doi:10.1083/jcb.200907037) demonstrate that the mitogen-activated protein kinase isoform p38-γ plays a crucial role in blocking the premature differentiation of satellite cells, a skeletal muscle stem cell population. p38-γ puts the brakes on skeletal muscle differentiation by promoting the association of the transcription factor MyoD with the histone methyltransferase, KMT1A, which act together in a complex to repress the premature expression of the gene encoding the myogenic transcription factor Myogenin.

Enhanced Human Hematopoietic Stem Cell Self-Renewal Enabled by Controlling Feedback Signaling From Lineage Committed Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1274-1274
Author(s):  
Elizabeth Csaszar ◽  
Daniel Kirouac ◽  
Mei Yu ◽  
Caryn Ito ◽  
Peter W. Zandstra
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cell Population ◽  
Ex Vivo ◽  
Stem Cell Population ◽  
Fed Batch ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Numbers

Abstract Abstract 1274 Clinical outcomes of hematopoietic stem cell (HSC) transplantation are correlated with infused progenitor cell dose. Limited cell numbers in a typical umbilical cord blood (UCB) unit restricts the therapeutic potential of UCB and motivates ex vivo expansion of these cells. Strategies to grow HSCs have relied on the supplement of molecules acting directly on the stem cell population; however, in all cases, sustained HSC growth is limited by the concurrent growth of more mature cells and their endogenously produced inhibitory signaling factors. Despite increasing evidence for the important role of intercellular (between cell) communication networks, the identity and impact of non-stem cell autonomous feedback signaling remains poorly understood. Simultaneous kinetic tracking of more than 30 secreted factors produced during UCB culture, including TGF-b1, MIP-1b, and MCP-1, in combination with computational simulations of cell population dynamics, enabled us to develop a global control strategy predicted to reduce inhibitory paracrine signaling and, consequently, increase HSC self-renewal. By maintaining endogenously produced ligands at specified levels using a tuneable fed-batch (automated media dilution) strategy, we achieved significant improvements in expansions of total cell numbers (∼180-fold), CD34+ cells (∼80-fold), and NOD/SCID/IL-2Rgc-null (NSG) repopulating cells (∼11-fold, detected at limiting dilution). The fed-batch strategy has been integrated into an automated bioreactor, allowing for the generation of a clinically-relevant cell product after 12 days of culture, with minimal user manipulation. As this strategy targets the HSC environment and not the stem cells directly, it has the ability to act in combination with other expansion strategies to produce synergistic results. Unexpectedly, supplementation of the soluble protein, TAT-HOXB4, to the system, yielded the expected boost in progenitor expansion only in “sub-optimal” control conditions but not in the fed-batch system. Hypothesizing that the efficacy of HOXB4 may be dependent on the skewing of supportive vs. non-supportive cell populations, and the consequent impact of paracrine ligand production, we performed kinetic tracking of 20 hematopoietic cell types during several supportive (fed-batch, HOXB4 supplemented, Notch ligand Delta1 supplemented) vs. non-supportive (control) cultures. Meta analysis of these data revealed a non-autonomous link between HOXB4, increased megakaryocyte production, and stem cell proliferation, as well as between Notch delta-1 ligand, decreased myeloid cell production, and a decrease in the growth inhibition of stem cells. These predictions have been experimentally validated using co-cultures of sorted purified HSCs and CD41+ megakaryocykes and CD14+ monocytes. Our results identify complex connections between mature cell lineages and stem cell fate decisions and we expect to report a direct link between cell-cell interactions emerging from culture manipulations and the resulting impact on HSC self-renewal. Collectively, these studies support a dominant role for non-stem cell autonomous feedback signaling in the regulation of HSC self-renewal. Overcoming cell non-autonomous inhibition of HSC self-renewal has allowed for novel strategies to enhance HSC numbers ex vivo, thereby facilitating the production of clinically relevant quantities of stem and progenitor cells and enabling more effective strategies to treat hematologic disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Molecular Regulation and Rejuvenation of Muscle Stem (Satellite) Cell Aging

2015 ◽  
Vol 7 (2) ◽  
pp. 73
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Satellite Cell ◽  
Muscle Mass ◽  
Satellite Cells ◽  
Cell Function ◽  
Muscle Stem Cell ◽  
Muscle Aging ◽  
Age Related

BACKGROUND: Age-related muscle loss leads to lack of muscle strength, resulting in reduced posture and mobility and an increased risk of falls, all of which contribute to a decrease in quality of life. Skeletal muscle regeneration is a complex process, which is not yet completely understood.CONTENT: Skeletal muscle undergoes a progressive age-related loss in mass and function. Preservation of muscle mass depends in part on satellite cells, the resident stem cells of skeletal muscle. Reduced satellite cell function may contribute to the age-associated decrease in muscle mass. Recent studies have delineated that the aging process in organ stem cells is largely caused by age-specific changes in the differentiated niches, and that regenerative outcomes often depend on the age of the niche, rather than on stem cell age. It is likely that epigenetic states will be better define such key satellite cell features as prolonged quiescence and lineage fidelity. It is also likely that DNA and histone modifications will underlie many of the changes in aged satellite cells that account for age-related declines in functionality and rejuvenation through exposure to the systemic environment.SUMMARY: Skeletal muscle aging results in a gradual loss of skeletal muscle mass, skeletal muscle function and regenerative capacity, which can lead to sarcopenia and increased mortality. Although the mechanisms underlying sarcopenia remain unclear, the skeletal muscle stem cell, or satellite cell, is required for muscle regeneration. Decreased muscle stem cell function in aging has long been shown to depend on altered environmental cues, whereas the contribution of intrinsic mechanisms remained less clear. Signals in the aged niche were shown to cause permanent defects in the ability of satellite cells to return to quiescence, ultimately also impairing the maintenance of self-renewing satellite cells. Therefore, only anti-aging strategies taking both factors, the stem cell niche and the stem cells per se, into consideration may ultimately be successful.KEYWORDS: satellite cell, muscle, aging, niche, regenerations

The Regenerating Skeletal Muscle Niche Guides Muscle Stem Cell Self-Renewal

2021 ◽  
Author(s):  
Alicia Ann Cutler ◽  
Bradley Pawlikowski ◽  
Joshua R. Wheeler ◽  
Nicole Carol Dalla Betta ◽  
Tiffany Antwine ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cell ◽  
Self Renewal ◽  
Muscle Stem Cell

scholarly journals Bipotent stem cells support the cyclical regeneration of endometrial epithelium of the murine uterus

2019 ◽  
Vol 116 (14) ◽  
pp. 6848-6857 ◽  
Author(s):  
Shiying Jin
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Population ◽  
Lineage Tracing ◽  
Tissue Loss ◽  
Stem Cell Population ◽  
Epithelial Stem Cells ◽  
Mouse Uterus ◽  
Epithelial Regeneration ◽  
Endometrial Epithelium

The endometrial epithelium of the uterus regenerates periodically. The cellular source of newly regenerated endometrial epithelia during a mouse estrous cycle or a human menstrual cycle is presently unknown. Here, I have used single-cell lineage tracing in the whole mouse uterus to demonstrate that epithelial stem cells exist in the mouse uterus. These uterine epithelial stem cells provide a resident cellular supply that fuels endometrial epithelial regeneration. They are able to survive cyclical uterine tissue loss and persistently generate all endometrial epithelial lineages, including the functionally distinct luminal and glandular epithelia, to maintain uterine cycling. The uterine epithelial stem cell population also supports the regeneration of uterine endometrial epithelium post parturition. The 5-ethynyl-2′-deoxyuridine pulse-chase experiments further reveal that this stem cell population may reside in the intersection zone between luminal and glandular epithelial compartments. This tissue distribution allows these bipotent uterine epithelial stem cells to bidirectionally differentiate to maintain homeostasis and regeneration of mouse endometrial epithelium under physiological conditions. Thus, uterine function over the reproductive lifespan of a mouse relies on stem cell-maintained rhythmic endometrial regeneration.

scholarly journals Long-Term Self-Renewal of Postnatal Muscle-derived Stem Cells

2005 ◽  
Vol 16 (7) ◽  
pp. 3323-3333 ◽  
Author(s):  
B. M. Deasy ◽  
B. M. Gharaibeh ◽  
J. B. Pollett ◽  
M. M. Jones ◽  
M. A. Lucas ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Muscle Regeneration ◽  
Replicative Senescence ◽  
Skeletal Muscle Regeneration ◽  
Cell Aging ◽  
Mdx Mice ◽  
Self Renewal

The ability to undergo self-renewal is a defining characteristic of stem cells. Self-replenishing activity sustains tissue homeostasis and regeneration. In addition, stem cell therapy strategies require a heightened understanding of the basis of the self-renewal process to enable researchers and clinicians to obtain sufficient numbers of undifferentiated stem cells for cell and gene therapy. Here, we used postnatal muscle-derived stem cells to test the basic biological assumption of unlimited stem cell replication. Muscle-derived stem cells (MDSCs) expanded for 300 population doublings (PDs) showed no indication of replicative senescence. MDSCs preserved their phenotype (ScaI+/CD34+/desminlow) for 200 PDs and were capable of serial transplantation into the skeletal muscle of mdx mice, which model Duchenne muscular dystrophy. MDSCs expanded to this level exhibited high skeletal muscle regeneration comparable with that exhibited by minimally expanded cells. Expansion beyond 200 PDs resulted in lower muscle regeneration, loss of CD34 expression, loss of myogenic activity, and increased growth on soft agar, suggestive of inevitable cell aging attributable to expansion and possible transformation of the MDSCs. Although these results raise questions as to whether cellular transformations derive from cell culturing or provide evidence of cancer stem cells, they establish the remarkable long-term self-renewal and regeneration capacity of postnatal MDSCs.

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