Tubastatin A maintains skeletal muscle stem cell (MuSC) quiescence
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA737274 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14800166_1.fastq.gz | Fastqsanger.gz | |||
| SRR14800166_2.fastq.gz | Fastqsanger.gz | |||
| SRR14800167_1.fastq.gz | Fastqsanger.gz | |||
| SRR14800167_2.fastq.gz | Fastqsanger.gz | |||
| SRR14800168_1.fastq.gz | Fastqsanger.gz |
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Project description:We show that Tubastatin A (TubA) preserves MuSC quiescence and stem cell potency ex vivo, by inhibiting HDAC6 and, consequently, primary cilium resorption. Treatment with TubA improves MuSC engraftment potential and induces a return to quiescence in cycling MuSCs, revealing a potentially valuable approach to enhancing the therapeutic potential of MuSCs. To examine the state of quiescence preserved by TubA at the transcriptome level, we performed RNA-Seq and we found that TubA-treated MuSCs exhibit a quiescent transcriptome. The molecular mechanisms involved in the maintenance of quiescence by TubA were ribosome- and oxidative phosphorylation-related genes as well as low expression levels of cell cycle genes and Hh signaling genes.
2022-01-28 | GSE178070 | GEO
Project description:Quiescent adult muscle stem cells (MuSCs) regenerate skeletal muscle upon injury throughout life. However, aged skeletal muscles fail to maintain stem cell quiescence, leading to declines in MuSC number and functionality. Although autophagy plays an important role in the maintenance of MuSC quiescence, how quiescent MuSCs and their autophagy levels are maintained throughout life is largely unknown. The current study reveals how GnRH, a hypothalamic hormone, maintains the quiescence of adult MuSCs by preventing the onset of senescence and how the decline of sex steroids in organismal ageing is implicated in MuSC ageing.
2019-10-05 | GSE121016 | GEO
Project description:Regeneration of skeletal muscle is dependent on the function of tissue-resident muscle stem cells (MuSC), known as satellite cells. MuSC dysfunction is central to muscle pathophysiology, including in age-associated loss of muscle regenerative capacity and congenital disorders such as Duchenne muscular dystrophy. Despite the central role of satellite cells in muscle regeneration, the signals controlling the balance between muscle stem cell quiescence, proliferation, and differentiation remain incompletely understood. Knowledge of the signals that maintain a quiescent state is particularly lacking, yet such cues are crucial to maintaining a stem cell reservoir that can meet the needs of regeneration throughout life. Here we identify Oncostatin M (OSM), a member of the interleukin-6 family of cytokines, as a potent and essential trans-acting regulator of satellite cell quiescence. Key to this discovery is the development of a novel in vivo imaging-based screening strategy allowing identification of proteins that do not induce in vitro proliferation, but instead maintain MuSCs in a non-mitotic state, poised for rapid robust expansion upon transplantation. We demonstrate that OSM induces reversible exit from the cell cycle and induction of a global transcriptional program significantly enriched within a newly established satellite cell “quiescence signature”. Genetic ablation of the OSM receptor in mice demonstrates that signaling via OSM/R is essential for maintenance of satellite cell quiescence, and for proper skeletal muscle regeneration in vivo. Given that aberrant activation and exhaustion of stem cells is seen in a variety of disorders, OSM constitutes an attractive therapeutic target in muscle disease states. Microarray profiling was used to directly test the hypothesis that OSMR signaling in muscle stem cells promotes their engraftment by inducing a global transcriptional state equivalent to that of quiescent, freshly isolated, non-activated MuSC.
2018-12-01 | GSE69976 | GEO
Project description:Adult muscle stem cells (MuSC) are quiescent with a localization between myofibers and basal lamina. Upon injury, MuSC exit quiescence, reenter cell cycle, expand and differentiate for muscle regeneration. By using genetic mouse model, we identified p110α/mTORC1 signaling as a indispensable pathway that permits quiescence exit and cell cycle reentry. In order to dig out the downstream effectors, we compared the transcriptome of freshly isolated MuSC from Ctrl (p110α-f/+:R26-YFP/YFP:Pax7-CreER/CreER) to MuSC-specific p110α-null (iKO, p110α-f/f:R26-YFP/YFP:Pax7-CreER/CreER) mice by RNA-sequencing, and AP1 target genes were dramatically down-regulated in iKO MuSC. Restoration of Jun could significantly rescue the cell cycle reentry defect in iKO MuSC. In summary, we provided a p110α/mTORC1/Jun axis required for quiecence exit and cell cycle reentry of MuSC.
2018-02-25 | GSE109472 | GEO
Project description:Background: Skeletal muscle crucially depends on motor innervation, and, when damaged, on the resident muscle stem cells (MuSCs). However, the role and function of MuSCs in the context of denervation remains poorly understood. Methods: Alterations of MuSCs and their myofiber niche after denervation were investigated in a surgery-based mouse model of unilateral sciatic nerve transection. FACS-isolated MuSCs were subjected to RNA-sequencing and mass spectrometry for the analysis of intrinsic changes after denervation and in vivo assays, such as Cardiotoxin-induced muscle injury or MuSC transplantation, were performed to assess MuSC functions after denervation. Bioinformatic and histological analyses were conducted to further examine MuSCs and their myofiber niche after denervation. Results: Muscle cross section analysis revealed a significant increase in Pax7 (p-value= 0.0441), Pax7/Ki67 (p-value= 0.0023), MyoD (p-value= 0.0016) and Myog (p-value= 0.0057) positive cells after denervation, illustrating a break of quiescence and commitment to the myogenic lineage. An Omics approach showed profound intrinsic alterations on the mRNA (2613 differentially expressed genes, p-value <0.05) and protein (1096 differentially abundant proteins, q-value <0.05) level of MuSCs 21 days after denervation. Skeletal muscle injury together with denervation surgery caused deregulated regeneration, indicated by the reduced number of proliferating MuSCs and sustained high levels of developmental myosin heavy chain (Sham: 1 % vs DEN: 40 % of all myofibers), at 21 days post-surgery. In a transplantation assay, MuSCs from a denervated host were still able to engraft and fuse to form new myofibers, irrespective of the innervation status of the recipient muscle. Analysis of myofibers revealed not only massive changes in the expression profile (10492 differentially expressed genes, p-value <0.05) after denervation, but it was also shown that secretion of Opn and Tgfb1 from denervated myofibers was increased 30-fold and 6000-fold, respectively. Bioinformatic analyses indicated strong upregulation of gene expression of the transcription factor Junb in MuSCs from denervated muscles (log2 fold change = 3.27). Of interest, Tgfb1 recombinant protein was able to induce Junb gene expression in vitro, demonstrating that myofiber-secreted ligands can induce gene expression changes in MuSCs, which might result in the phenotypes observed after denervation. Conclusion: Skeletal muscle denervation is altering myofiber secretion, causing MuSC activation and profound intrinsic changes, leading to reduced regenerative capacity. As MuSCs possess a remarkable regenerative potential, they might represent a promising target for novel treatment options for neuromuscular disorders and peripheral nerve injuries.
2024-02-27 | PXD036993 | Pride
Project description:Organismal homeostasis and regeneration are predicated on committed stem cells which, in tissues and organs with low turnover, reside for long periods in a reversible cell cycle arrest, defined as quiescence. Inability to exit or premature escape from quiescence, as occurring in pathological conditions and aging, is detrimental as it results in either lack of stem cell mobilization or pool depletion with consequent defective tissue homeostatis and regeneration. It is therefore unsurprising that quiescence is safeguarded by multilayered regulatory mechanisms. Here, we report that Polycomb Ezh1 confers quiescence to muscle stem cells (MuSCs) through a non-canonical function. In the absence of Ezh1, MuSCs spontaneously exit quiescence and, following repeated injuries, the stem cell pool is depleted resulting in failure to sustain appropriate muscle regeneration. Rather than regulating repressive Polycomb-dependent histone H3K27 methylation, Ezh1 actively maintains the Notch signaling pathway in MuSCs. Accordingly, selective genetic reconstitution of the Notch signaling corrects stem cell number and re-establishes quiescence of Ezh1-/- MuSCs.
2023-04-04 | GSE219232 | GEO
Project description:Skeletal muscle stem cells (MuSCs) ensure the formation and homeostasis of skeletal muscle and are responsible for its growth and repair processes. For repair to occur, MuSCs must exit from quiescence, abandon their niche and asymmetrically and symmetrically divide to reconstitute the stem cell pool and give rise to muscle progenitors, respectively. The transcriptomes of pooled MuSCs have provided a rich source of information for describing the genetic programs underlying distinct static cell states; however, bulk microarray and RNA-seq afford only averaged gene expression profiles, which blur the heterogeneity and developmental dynamics of asynchronous MuSC populations. The granularity required to identify distinct cell types, states, and their dynamics can be provided by single-cell analysis. We were able to compare the transcriptomes of thousands of MuSCs and primary myoblasts isolated from homeostatic or regenerating muscles by single-cell RNA- sequencing. Using computational approaches, we could reconstruct dynamic trajectories and place, in a pseudotemporal manner, the transcriptomes of individual MuSC within these trajectories. This approach allowed for the identification of distinct clusters of MuSCs and primary myoblasts with partially overlapping but distinct transcriptional signatures, as well as the description of metabolic pathways associated with defined MuSC states.
2019-03-08 | GSE126834 | GEO
Project description:The requirement for microRNAs in muscle homeostasis, and more precisely in quiescence/self-renewal, activation & differentiation, has been demonstrated through knock-out experiments. In this experiment, we unbiasedly probed the expression of small RNA molecules (ranging from 18-36 nt in size), during the quiescence/activation transition but also differentiation by mean of small-RNA sequencing. Quiescent cells were directly FACS-purified from resting muscle of tg:Pax7-nGFP adult mice (n=2 replicates), and a fraction of these sorted cells were cultured in vitro to obtain activated MuSC at 60h, or differentiated cells at 7 days. This dataset constitutes a key resource for further analyses of miRNAs involvement in the muscle paradigm, and more largely in the regulation of stem cells self-renewal and tissue homeostasis.
2018-03-24 | E-MTAB-5955 | biostudies-arrayexpress
Project description:Adhesion between stem cells and their niche promotes stable niche localization and provides signaling information to sustain properties such as quiescence. Skeletal muscle stem cells (MuSCs) are localized between an adjacent myofiber and an enwrapping basal lamina. The most abundant cadherin in MuSCs, M-cadherin, is dispensable for MuSC function, whereas N-cadherin is required to prevent MuSCs from breaking quiescence in the absence of injury. Loss of both cadherins exacerbates this phenotype, yet the MuSCs remain in the niche and maintain regenerative function. These findings raise the possibility that cadherins are dispensable for anchorage of MuSCs to their niche. To address this question, we conditionally removed from MuSCs b- and g-catenin and, separately, aE- and aT-catenin, factors essential for cadherin-dependent adhesion. Catenin-deficient MuSCs break quiescence similarly to N-/M-cadherin-deficient MuSCs, but exit the niche, and are depleted via a single fate: precocious differentiation, reentry to the niche, and fusion to myofibers. These findings indicate that separable, cadherin-dependent functions are required in MuSCs for niche localization, quiescence, and stem cell maintenance.
2024-03-07 | GSE244181 | GEO
Project description:Three-dimensional tissue-engineered human skeletal muscle model of satellite cell quiescence
| PRJNA777926 | ENA