Drosophila, an Integrative Model to Study the Features of Muscle Stem Cells in Development and Regeneration

Muscle stem cells (MuSCs) are essential for muscle growth, maintenance and repair. Over the past decade, experiments in Drosophila have been instrumental in understanding the molecular and cellular mechanisms regulating MuSCs (also known as adult muscle precursors, AMPs) during development. A large number of genetic tools available in fruit flies provides an ideal framework to address new questions which could not be addressed with other model organisms. This review reports the main findings revealed by the study of Drosophila AMPs, with a specific focus on how AMPs are specified and properly positioned, how they acquire their identity and which are the environmental cues controlling their behavior and fate. The review also describes the recent identification of the Drosophila adult MuSCs that have similar characteristics to vertebrates MuSCs. Integration of the different levels of MuSCs analysis in flies is likely to provide new fundamental knowledge in muscle stem cell biology largely applicable to other systems.

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Empowering Muscle Stem Cells for the Treatment of Duchenne Muscular Dystrophy

Cells Tissues Organs ◽

10.1159/000514305 ◽

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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Skeletal Muscle Stem Cells from Animals I. Basic Cell Biology

International Journal of Biological Sciences ◽

10.7150/ijbs.6.465 ◽

2010 ◽

pp. 465-474 ◽

Cited By ~ 36

Author(s):

Michael V. Dodson ◽

Gary J. Hausman ◽

LeLuo Guan ◽

Min Du ◽

Theodore P. Rasmussen ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Cell Biology ◽

Muscle Stem Cells ◽

Basic Cell ◽

Skeletal Muscle Stem Cells

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Loss of Ptpn11 (Shp2) drives satellite cells into quiescence

eLife ◽

10.7554/elife.21552 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 5

Author(s):

Joscha Griger ◽

Robin Schneider ◽

Ines Lahmann ◽

Verena Schöwel ◽

Charles Keller ◽

...

Keyword(s):

Stem Cells ◽

Tyrosine Phosphatase ◽

Muscle Growth ◽

Cell Activity ◽

Muscle Stem Cells ◽

Myogenic Stem Cells ◽

Postnatal Myogenesis ◽

Receptor Tyrosine Phosphatase ◽

Satellite Cell Activity

The equilibrium between proliferation and quiescence of myogenic progenitor and stem cells is tightly regulated to ensure appropriate skeletal muscle growth and repair. The non-receptor tyrosine phosphatase Ptpn11 (Shp2) is an important transducer of growth factor and cytokine signals. Here we combined complex genetic analyses, biochemical studies and pharmacological interference to demonstrate a central role of Ptpn11 in postnatal myogenesis of mice. Loss of Ptpn11 drove muscle stem cells out of the proliferative and into a resting state during muscle growth. This Ptpn11 function was observed in postnatal but not fetal myogenic stem cells. Furthermore, muscle repair was severely perturbed when Ptpn11 was ablated in stem cells due to a deficit in stem cell proliferation and survival. Our data demonstrate a molecular difference in the control of cell cycle withdrawal in fetal and postnatal myogenic stem cells, and assign to Ptpn11 signaling a key function in satellite cell activity.

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Oscillations of Delta-like1 regulate the balance between differentiation and maintenance of muscle stem cells

Nature Communications ◽

10.1038/s41467-021-21631-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yao Zhang ◽

Ines Lahmann ◽

Katharina Baum ◽

Hiromi Shimojo ◽

Philippos Mourikis ◽

...

Keyword(s):

Stem Cells ◽

Muscle Growth ◽

Regulatory Factor ◽

Self Renewal ◽

Muscle Stem Cells ◽

Cell Pool ◽

Cellular Source ◽

Skeletal Muscle Stem Cells ◽

Notch Ligands ◽

Stem Cell Pool

AbstractCell-cell interactions mediated by Notch are critical for the maintenance of skeletal muscle stem cells. However, dynamics, cellular source and identity of functional Notch ligands during expansion of the stem cell pool in muscle growth and regeneration remain poorly characterized. Here we demonstrate that oscillating Delta-like 1 (Dll1) produced by myogenic cells is an indispensable Notch ligand for self-renewal of muscle stem cells in mice. Dll1 expression is controlled by the Notch target Hes1 and the muscle regulatory factor MyoD. Consistent with our mathematical model, our experimental analyses show that Hes1 acts as the oscillatory pacemaker, whereas MyoD regulates robust Dll1 expression. Interfering with Dll1 oscillations without changing its overall expression level impairs self-renewal, resulting in premature differentiation of muscle stem cells during muscle growth and regeneration. We conclude that the oscillatory Dll1 input into Notch signaling ensures the equilibrium between self-renewal and differentiation in myogenic cell communities.

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The transcription factor NF-Y participates to stem cell fate decision and regeneration in adult skeletal muscle

Nature Communications ◽

10.1038/s41467-021-26293-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Giovanna Rigillo ◽

Valentina Basile ◽

Silvia Belluti ◽

Mirko Ronzio ◽

Elisabetta Sauta ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Transcription Factor ◽

Stem Cell ◽

Satellite Cells ◽

Cell Biology ◽

Myogenic Differentiation ◽

Stem Cell Population ◽

Adult Skeletal Muscle ◽

Muscle Stem Cells

AbstractThe transcription factor NF-Y promotes cell proliferation and its activity often declines during differentiation through the regulation of NF-YA, the DNA binding subunit of the complex. In stem cell compartments, the shorter NF-YA splice variant is abundantly expressed and sustains their expansion. Here, we report that satellite cells, the stem cell population of adult skeletal muscle necessary for its growth and regeneration, express uniquely the longer NF-YA isoform, majorly associated with cell differentiation. Through the generation of a conditional knock out mouse model that selectively deletes the NF-YA gene in satellite cells, we demonstrate that NF-YA expression is fundamental to preserve the pool of muscle stem cells and ensures robust regenerative response to muscle injury. In vivo and ex vivo, satellite cells that survive to NF-YA loss exit the quiescence and are rapidly committed to early differentiation, despite delayed in the progression towards later states. In vitro results demonstrate that NF-YA-depleted muscle stem cells accumulate DNA damage and cannot properly differentiate. These data highlight a new scenario in stem cell biology for NF-Y activity, which is required for efficient myogenic differentiation.

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METTL3-Mediated m6A Methylation Regulates Muscle Stem Cells and Muscle Regeneration by Notch Signaling Pathway

Stem Cells International ◽

10.1155/2021/9955691 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Yu Liang ◽

Hui Han ◽

Qiuchan Xiong ◽

Chunlong Yang ◽

Lu Wang ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Notch Signaling ◽

Signaling Pathway ◽

Muscle Regeneration ◽

Mrna Translation ◽

Notch Signaling Pathway ◽

Muscle Stem Cell ◽

Muscle Stem Cells

The Pax7+ muscle stem cells (MuSCs) are essential for skeletal muscle homeostasis and muscle regeneration upon injury, while the molecular mechanisms underlying muscle stem cell fate determination and muscle regeneration are still not fully understood. N6-methyladenosine (m6A) RNA modification is catalyzed by METTL3 and plays important functions in posttranscriptional gene expression regulation and various biological processes. Here, we generated muscle stem cell-specific METTL3 conditional knockout mouse model and revealed that METTL3 knockout in muscle stem cells significantly inhibits the proliferation of muscle stem cells and blocks the muscle regeneration after injury. Moreover, knockin of METTL3 in muscle stem cells promotes the muscle stem cell proliferation and muscle regeneration in vivo. Mechanistically, METTL3-m6A-YTHDF1 axis regulates the mRNA translation of Notch signaling pathway. Our data demonstrated the important in vivo physiological function of METTL3-mediated m6A modification in muscle stem cells and muscle regeneration, providing molecular basis for the therapy of stem cell-related muscle diseases.

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

Stem Cells International ◽

10.1155/2016/5725927 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 26

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.

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Progressive and Coordinated Mobilization of the Skeletal Muscle Niche throughout Tissue Repair Revealed by Single-Cell Proteomic Analysis

Cells ◽

10.3390/cells10040744 ◽

2021 ◽

Vol 10 (4) ◽

pp. 744

Author(s):

Matthew Borok ◽

Nathalie Didier ◽

Francesca Gattazzo ◽

Teoman Ozturk ◽

Aurelien Corneau ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Stem Cell ◽

Muscle Regeneration ◽

Cell Types ◽

Skeletal Muscle Regeneration ◽

Muscle Repair ◽

Muscle Stem Cell ◽

Muscle Stem Cells ◽

Cell Lineages

Background: Skeletal muscle is one of the only mammalian tissues capable of rapid and efficient regeneration after trauma or in pathological conditions. Skeletal muscle regeneration is driven by the muscle satellite cells, the stem cell population in interaction with their niche. Upon injury, muscle fibers undergo necrosis and muscle stem cells activate, proliferate and fuse to form new myofibers. In addition to myogenic cell populations, interaction with other cell types such as inflammatory cells, mesenchymal (fibroadipogenic progenitors—FAPs, pericytes) and vascular (endothelial) lineages are important for efficient muscle repair. While the role of the distinct populations involved in skeletal muscle regeneration is well characterized, the quantitative changes in the muscle stem cell and niche during the regeneration process remain poorly characterized. Methods: We have used mass cytometry to follow the main muscle cell types (muscle stem cells, vascular, mesenchymal and immune cell lineages) during early activation and over the course of muscle regeneration at D0, D2, D5 and D7 compared with uninjured muscles. Results: Early activation induces a number of rapid changes in the proteome of multiple cell types. Following the induction of damage, we observe a drastic loss of myogenic, vascular and mesenchymal cell lineages while immune cells invade the damaged tissue to clear debris and promote muscle repair. Immune cells constitute up to 80% of the mononuclear cells 5 days post-injury. We show that muscle stem cells are quickly activated in order to form new myofibers and reconstitute the quiescent muscle stem cell pool. In addition, our study provides a quantitative analysis of the various myogenic populations during muscle repair. Conclusions: We have developed a mass cytometry panel to investigate the dynamic nature of muscle regeneration at a single-cell level. Using our panel, we have identified early changes in the proteome of stressed satellite and niche cells. We have also quantified changes in the major cell types of skeletal muscle during regeneration and analyzed myogenic transcription factor expression in satellite cells throughout this process. Our results highlight the progressive dynamic shifts in cell populations and the distinct states of muscle stem cells adopted during skeletal muscle regeneration. Our findings give a deeper understanding of the cellular and molecular aspects of muscle regeneration.

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Human muscle-derived CLEC14A-positive cells regenerate muscle independent of PAX7

Nature Communications ◽

10.1038/s41467-019-13650-z ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

Andreas Marg ◽

Helena Escobar ◽

Nikos Karaiskos ◽

Stefanie A. Grunwald ◽

Eric Metzler ◽

...

Keyword(s):

Stem Cells ◽

Muscle Growth ◽

Human Muscle ◽

Muscle Stem Cells ◽

Regenerate Muscle ◽

Endothelial Cell Marker ◽

Satellite Cell Niche ◽

Cell Niche ◽

Skeletal Muscle Stem Cells ◽

Myogenic Markers

AbstractSkeletal muscle stem cells, called satellite cells and defined by the transcription factor PAX7, are responsible for postnatal muscle growth, homeostasis and regeneration. Attempts to utilize the regenerative potential of muscle stem cells for therapeutic purposes so far failed. We previously established the existence of human PAX7-positive cell colonies with high regenerative potential. We now identified PAX7-negative human muscle-derived cell colonies also positive for the myogenic markers desmin and MYF5. These include cells from a patient with a homozygous PAX7 c.86-1G > A mutation (PAX7null). Single cell and bulk transcriptome analysis show high intra- and inter-donor heterogeneity and reveal the endothelial cell marker CLEC14A to be highly expressed in PAX7null cells. All PAX7-negative cell populations, including PAX7null, form myofibers after transplantation into mice, and regenerate muscle after reinjury. Transplanted PAX7neg cells repopulate the satellite cell niche where they re-express PAX7, or, strikingly, CLEC14A. In conclusion, transplanted human cells do not depend on PAX7 for muscle regeneration.

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Old knowledge and new technologies allow rapid development of model organisms

Molecular Biology of the Cell ◽

10.1091/mbc.e15-10-0682 ◽

2016 ◽

Vol 27 (6) ◽

pp. 882-887 ◽

Cited By ~ 11

Author(s):

Charles E. Cook ◽

Janet Chenevert ◽

Tomas A. Larsson ◽

Detlev Arendt ◽

Evelyn Houliston ◽

...

Keyword(s):

Cell Biology ◽

High Throughput Sequencing ◽

Biological Diversity ◽

New Technologies ◽

Low Cost ◽

Rapid Development ◽

Experimental Models ◽

Model Organisms ◽

Model Species ◽

Cellular Mechanisms

Until recently the set of “model” species used commonly for cell biology was limited to a small number of well-understood organisms, and developing a new model was prohibitively expensive or time-consuming. With the current rapid advances in technology, in particular low-cost high-throughput sequencing, it is now possible to develop molecular resources fairly rapidly. Wider sampling of biological diversity can only accelerate progress in addressing cellular mechanisms and shed light on how they are adapted to varied physiological contexts. Here we illustrate how historical knowledge and new technologies can reveal the potential of nonconventional organisms, and we suggest guidelines for selecting new experimental models. We also present examples of nonstandard marine metazoan model species that have made important contributions to our understanding of biological processes.

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