Relayed signaling between mesenchymal progenitors and muscle stem cells ensures adaptive stem cell response to increased mechanical load

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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Dose-Independent Therapeutic Benefit of Bone Marrow Stem Cell Transplantation after MI in Mice

Biomedicines ◽

10.3390/biomedicines8060157 ◽

2020 ◽

Vol 8 (6) ◽

pp. 157

Author(s):

Nicole Zarniko ◽

Anna Skorska ◽

Gustav Steinhoff ◽

Robert David ◽

Ralf Gaebel

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Ex Vivo ◽

Therapeutic Benefit ◽

Dependent Manner ◽

Mesenchymal Progenitors

Several cell populations derived from bone marrow (BM) have been shown to possess cardiac regenerative potential. Among these are freshly isolated CD133+ hematopoietic as well as culture-expanded mesenchymal stem cells. Alternatively, by purifying CD271+ cells from BM, mesenchymal progenitors can be enriched without an ex vivo cultivation. With regard to the limited available number of freshly isolated BM-derived stem cells, the effect of the dosage on the therapeutic efficiency is of particular interest. Therefore, in the present pre-clinical study, we investigated human BM-derived CD133+ and CD271+ stem cells for their cardiac regenerative potential three weeks post-myocardial infarction (MI) in a dose-dependent manner. The improvement of the hemodynamic function as well as cardiac remodeling showed no therapeutic difference after the transplantation of both 100,000 and 500,000 stem cells. Therefore, beneficial stem cell transplantation post-MI is widely independent of the cell dose and detrimental stem cell amplification in vitro can likely be avoided.

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APC is required for muscle stem cell proliferation and skeletal muscle tissue repair

The Journal of Cell Biology ◽

10.1083/jcb.201501053 ◽

2015 ◽

Vol 210 (5) ◽

pp. 717-726 ◽

Cited By ~ 27

Author(s):

Alice Parisi ◽

Floriane Lacour ◽

Lorenzo Giordani ◽

Sabine Colnot ◽

Pascal Maire ◽

...

Keyword(s):

Cell Cycle ◽

Skeletal Muscle ◽

Stem Cells ◽

Stem Cell ◽

Cell Cycle Progression ◽

Cell Types ◽

Double Knockout ◽

Muscle Stem Cells ◽

Adult Muscle ◽

Canonical Wnt

The tumor suppressor adenomatous polyposis coli (APC) is a crucial regulator of many stem cell types. In constantly cycling stem cells of fast turnover tissues, APC loss results in the constitutive activation of a Wnt target gene program that massively increases proliferation and leads to malignant transformation. However, APC function in skeletal muscle, a tissue with a low turnover rate, has never been investigated. Here we show that conditional genetic disruption of APC in adult muscle stem cells results in the abrogation of adult muscle regenerative potential. We demonstrate that APC removal in adult muscle stem cells abolishes cell cycle entry and leads to cell death. By using double knockout strategies, we further prove that this phenotype is attributable to overactivation of β-catenin signaling. Our results demonstrate that in muscle stem cells, APC dampens canonical Wnt signaling to allow cell cycle progression and radically diverge from previous observations concerning stem cells in actively self-renewing tissues.

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Pro-myogenic small molecules revealed by a chemical screen on primary muscle stem cells

Skeletal Muscle ◽

10.1186/s13395-020-00248-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sean M. Buchanan ◽

Feodor D. Price ◽

Alessandra Castiglioni ◽

Amanda Wagner Gee ◽

Joel Schneider ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Stem Cell ◽

Small Molecules ◽

Satellite Cell ◽

Satellite Cells ◽

Muscle Repair ◽

Muscle Stem Cells

Abstract Satellite cells are the canonical muscle stem cells that regenerate damaged skeletal muscle. Loss of function of these cells has been linked to reduced muscle repair capacity and compromised muscle health in acute muscle injury and congenital neuromuscular diseases. To identify new pathways that can prevent loss of skeletal muscle function or enhance regenerative potential, we established an imaging-based screen capable of identifying small molecules that promote the expansion of freshly isolated satellite cells. We found several classes of receptor tyrosine kinase (RTK) inhibitors that increased freshly isolated satellite cell numbers in vitro. Further exploration of one of these compounds, the RTK inhibitor CEP-701 (also known as lestaurtinib), revealed potent activity on mouse satellite cells both in vitro and in vivo. This expansion potential was not seen upon exposure of proliferating committed myoblasts or non-myogenic fibroblasts to CEP-701. When delivered subcutaneously to acutely injured animals, CEP-701 increased both the total number of satellite cells and the rate of muscle repair, as revealed by an increased cross-sectional area of regenerating fibers. Moreover, freshly isolated satellite cells expanded ex vivo in the presence of CEP-701 displayed enhanced muscle engraftment potential upon in vivo transplantation. We provide compelling evidence that certain RTKs, and in particular RET, regulate satellite cell expansion during muscle regeneration. This study demonstrates the power of small molecule screens of even rare adult stem cell populations for identifying stem cell-targeting compounds with therapeutic potential.

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

Nature Communications ◽

10.1038/s41467-019-12293-4 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 37

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.

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Controlling Self-Renewal and Differentiation of Stem Cells via Mechanical Cues

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/797410 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 85

Author(s):

Michele M. Nava ◽

Manuela T. Raimondi ◽

Riccardo Pietrabissa

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Fate ◽

Cell Response ◽

Recent Literature ◽

Focal Adhesions ◽

Substrate Stiffness ◽

Self Renewal ◽

Mechanical Factors

The control of stem cell responsein vitro, including self-renewal and lineage commitment, has been proved to be directed by mechanical cues, even in the absence of biochemical stimuli. Through integrin-mediated focal adhesions, cells are able to anchor onto the underlying substrate, sense the surrounding microenvironment, and react to its properties. Substrate-cell and cell-cell interactions activate specific mechanotransduction pathways that regulate stem cell fate. Mechanical factors, including substrate stiffness, surface nanotopography, microgeometry, and extracellular forces can all have significant influence on regulating stem cell activities. In this paper, we review all the most recent literature on the effect of purely mechanical cues on stem cell response, and we introduce the concept of “force isotropy” relevant to cytoskeletal forces and relevant to extracellular loads acting on cells, to provide an interpretation of how the effects of insoluble biophysical signals can be used to direct stem cells fatein vitro.

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Aging induces aberrant state transition kinetics in murine muscle stem cells

10.1101/739185 ◽

2019 ◽

Cited By ~ 2

Author(s):

Jacob C. Kimmel ◽

Ara B. Hwang ◽

Wallace F. Marshall ◽

Andrew S. Brack

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Activation ◽

Cell Function ◽

Cell Phenotype ◽

Cell Dynamics ◽

Muscle Stem Cells ◽

Cell Age ◽

Activation Dynamics ◽

Summary Statement

AbstractMurine muscle stem cells (MuSCs) experience a transition from quiescence to activation that is required for regeneration, but it remains unclear if the transition states and rates of activation are uniform across cells, or how features of this process may change with age. Here, we use timelapse imaging and single cell RNA-seq to measure activation trajectories and rates in young and aged MuSCs. We find that the activation trajectory is conserved in aged cells, and develop effective machine learning classifiers for cell age. Using cell behavior analysis and RNA velocity, we find that activation kinetics are delayed in aged MuSCs, suggesting that changes in stem cell dynamics may contribute to impaired stem cell function with age. Intriguingly, we also find that stem cell activation appears to be a random walk like process, with frequent reversals, rather than a continuous, linear progression. These results support a view of the aged stem cell phenotype as a combination of differences in the location of stable cell states and differences in transition rates between them.Summary StatementWe find that aged muscle stem cells display delayed activation dynamics, but retain a youthful activation trajectory, suggesting that changes to cell state dynamics may contribute to aging pathology.

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