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

2015 ◽  
Vol 210 (5) ◽  
pp. 717-726 ◽  
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.

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

Cells ◽  
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.

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 R-spondin1 regulates muscle progenitor cell fusion through control of antagonist Wnt signaling pathways

2016 ◽  
Author(s):  
Floriane Lacour ◽  
Elsa Vezin ◽  
Florian Bentzinger ◽  
Marie-Claude Sincennes ◽  
Robert D. Mitchell ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Signaling Pathways ◽  
Muscle Regeneration ◽  
Muscle Cells ◽  
Skeletal Muscle Regeneration ◽  
Acute Injury ◽  
Canonical Wnt

SUMMARYTissue regeneration requires the selective activation and repression of specific signaling pathways in stem cells. As such, the Wnt signaling pathways have been shown to control stem cell fate. In many cell types, the R-Spondin (Rspo) family of secreted proteins acts as potent activators of the canonical Wnt/β-catenin pathway. Here, we identify Rspo1 as a mediator of skeletal muscle tissue repair. Firstly we show that Rspo1-null muscles do not display any abnormalities at the basal level. However deletion of Rspo1 results in global alteration of muscle regeneration kinetics following acute injury. We found that muscle stem cells lacking Rspo1 show delayed differentiation. Transcriptome analysis further demonstrated that Rspo1 is required for the activation of Wnt/β-catenin target genes in muscle cells. Furthermore, muscle cells lacking Rspo1 fuse with a higher frequency than normal cells, leading to larger myotubes containing more nuclei both in vitro and in vivo. We found the increase in muscle fusion was dependent on up-regulation of non-canonical Wnt7a/Fzd7/Rac1 signaling. We conclude that antagonistic control of canonical and non-canonical Wnt signaling pathways by Rspo1 in muscle stem cell progeny is important for restitution of normal muscle architecture during skeletal muscle regeneration.

scholarly journals Changes in ionizing radiation dose rate affect cell cycle progression in adipose derived stem cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250160
Author(s):  
Matthew Rusin ◽  
Nardine Ghobrial ◽  
Endre Takacs ◽  
Jeffrey S. Willey ◽  
Delphine Dean
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Radiation Therapy ◽  
Stem Cell ◽  
Regenerative Medicine ◽  
Ionizing Radiation ◽  
Dose Rate ◽  
Cell Types ◽  
High Energy ◽  
Adipose Derived Stem Cells

Biomedical use of radiation is utilized in effective diagnostic and treatment tools, yet can introduce risks to healthy tissues. High energy photons used for diagnostic purposes have high penetration depth and can discriminate multiple tissues based on attenuation properties of different materials. Likewise, the ability to deposit energy at various targets within tumors make the use of photons effective treatment for cancer. Radiation focused on a tumor will deposit energy when it interacts with a biological structure (e.g. DNA), which will result in cell kill should repair capacity of the tissue be overwhelmed. Likewise, damage to normal, non-cancerous tissues is a consequence of radiation that can lead to acute or late, chronic toxicity profiles. Adipose derived stem cells (ADSCs) are mesenchymal stem cells that have been proven to have similar characteristics to bone marrow derived stem cells, except that they are much easier to obtain. Within the body, ADSCs act as immunomodulators and assist with the maintenance and repair of tissues. They have been shown to have excellent differentiation capability, making them an extremely viable option for stem cell therapies and regenerative medicine applications. Due to the tissue ADSCs are derived from, they are highly likely to be affected by radiation therapy, especially when treating tumors localized to structures with relatively high ADSC content (eg., breast cancer). For this reason, the purpose behind this research is to better understand how ADSCs are affected by doses of radiation comparable to a single fraction of radiation therapy. We also measured the response of ADSCs to exposure at different dose rates to determine if there is a significant difference in the response of ADSCs to radiation therapy relevant doses of ionizing radiation. Our findings indicate that ADSCs exposed to Cesium (Cs 137)-gamma rays at a moderate dose of 2Gy and either a low dose rate (1.40Gy/min) or a high dose rate (7.31Gy/min) slow proliferation rate, and with cell cycle arrest in some populations. These responses ADSCs were not as marked as previously measured in other stem cell types. In addition, our results indicate that differences in dose rate in the Gy/min range typically utilized in small animal or cell irradiation platforms have a minimal effect on the function of ADSCs. The potential ADSCs have in the space of regenerative medicine makes them an ideal candidate for study with ionizing radiation, as they are one of the main cell types to promote tissue healing.

scholarly journals Cell cycle exit and stem cell differentiation are coupled through regulation of mitochondrial activity in the Drosophila testis

2021 ◽  
Author(s):  
Diego Sainz de la Maza ◽  
Silvana Hof-Michel ◽  
Lee Phillimore ◽  
Christian Bökel ◽  
Marc Amoyel
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Cycle Progression ◽  
Stem Cell Differentiation ◽  
Mitochondrial Activity ◽  
Self Renewal ◽  
Cycle Progression ◽  
Cell Identity ◽  
Drosophila Testis

AbstractStem cells maintain tissue homeostasis by proliferating to replace cells lost to damage or natural turnover. Whereas stem and progenitor cells proliferate, fully differentiated cells exit the cell cycle. How cell identity and cell cycle state are coordinated during this process is still poorly understood. The Drosophila testis niche supports germline stem cells and somatic cyst stem cells (CySCs), which are the only proliferating somatic cells in the testis. CySCs give rise to post-mitotic cyst cells and therefore provide a tractable model to ask how stem cell identity is linked to proliferation. We show that the G1/S cyclin, Cyclin E, is required for CySC self-renewal; however, its canonical transcriptional regulator, a complex of the E2f1 and Dp transcription factors is dispensable for self-renewal and cell cycle progression. Nevertheless, we demonstrate that E2f1/Dp activity must be silenced to allow CySCs to differentiate. We show that E2f1/Dp activity inhibits the expression of genes important for mitochondrial activity. Furthermore, promoting mitochondrial activity or biogenesis is sufficient to rescue the differentiation of CySCs with ectopic E2f1/Dp activity but not their exit from the cell cycle. Our findings together indicate that E2f1/Dp coordinates cell cycle progression with stem cell identity by regulating the metabolic state of CySCs.

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

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.

scholarly journals Cell Cycle-Driven Heterogeneity: On the Road to Demystifying the Transitions between “Poised” and “Restricted” Pluripotent Cell States

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Amar M. Singh
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cells ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
The Road ◽  
Developmental Factors ◽  
On The Road ◽  
G1 Cells

Cellular heterogeneity is now considered an inherent property of most stem cell types, including pluripotent stem cells, somatic stem cells, and cancer stem cells, and this heterogeneity can exist at the epigenetic, transcriptional, and posttranscriptional levels. Several studies have indicated that the stochastic activation of signaling networks may promote heterogeneity and further that this heterogeneity may be reduced by their inhibition. But why different cells in the same culture respond in a nonuniform manner to the identical exogenous signals has remained unclear. Recent studies now demonstrate that the cell cycle position directly influences lineage specification and specifically that pluripotent stem cells initiate their differentiation from the G1 phase. These studies suggest that cells in G1 are uniquely “poised” to undergo cell specification. G1 cells are therefore more prone to respond to differentiation cues, which may explain the heterogeneity of developmental factors, such as Gata6, and pluripotency factors, such as Nanog, in stem cell cultures. Overall, this raises the possibility that G1 serves as a “Differentiation Induction Point.” In this review, we will reexamine the literature describing heterogeneity of pluripotent stem cells, while highlighting the role of the cell cycle as a major determinant.

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

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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