Sex hormones control muscle stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE121016 | GEO | 2019/10/05
REPOSITORIES: GEO
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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: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: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: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:Regulation of quiescence is essential for adult stem cell maintenance, longevity and sustained regeneration potential. Our studies have uncovered that physiological and transient changes in mitochondrial shape regulate the quiescent state of adult muscle stem cells (MuSCs). We show that mitochondria in MuSCs rapidly fragment in response to an activation stimulus, via a systemic HGF/mTOR mechanism, to drive the exit from deep quiescence. Deletion of the mitochondrial fusion protein OPA1 and forced mitochondrial fragmentation is sufficient to transition MuSCs into G-alert quiescence causing premature activation and depletion upon a stimulus. Loss of OPA1 activates a glutathione (GSH) redox signaling pathway that promotes cell-cycle progression, myogenic gene expression and commitment. MuSCs with chronic OPA1 loss and mitochondrial fragmentation, leading to mitochondrial dysfunction, continue to reside in a primed state but acquire severe cell cycle defects. Additionally, we provide evidence that OPA1 decline and impaired mitochondrial dynamics may contribute to age-related MuSC dysfunction. These findings reveal a fundamental role for OPA1 and mitochondrial dynamics in establishing the quiescent state and activation potential of adult stem cells.
2022-08-24 | GSE208326 | GEO
Project description:To uncover new pathways that are important for skeletal muscle stem cell (MuSC) aging, we performed multiomics profiling, including transcriptomics, DNA methylomics, proteomics, and metabolomics on quiescent MuSCs from young and old mice. Our goals were to discover pathways that have been overlooked by isolated profiling approaches and to gain insight into which changes are causal, compensatory, correlational, and consequential. In our work, we found that glutathione metabolism is a key pathway of MuSC that involves a compensatory feedback loop. Follow-up experiments showed that old MuSCs actually form a dichotomy between glutathione-high MuSCs and glutathione-low MuSCs. RNA-Seq showed that glutathione-high old MuSCs are able to synthesize adequate glutathione and thus compensate adequately for oxidative stress with increased glutathione turnover, while glutathione-low old MuSCs have failed to compensate for oxidative stress metabolically and instead show increased inflammatory signaling.
2023-03-20 | GSE152796 | GEO
Project description:Short-term fasting is beneficial for the regeneration of multiple tissue types. However, the effects of fasting on muscle regeneration are largely unknown. Here we report that fasting slows muscle repair both immediately after the conclusion of fasting as well as after multiple days of refeeding. We show that ketosis, either endogenously produced during fasting or a ketogenic diet, or exogenously administered, promotes a deep quiescent state in MuSCs. Although deep quiescent MuSCs are less poised to activate, slowing muscle regeneration, they have markedly improved survival when facing sources of cellular stress. Further, we show that ketone bodies, specifically b- hydroxybutyrate, directly promote MuSC deep quiescence via a non‐metabolic mechanism. We show that b-hydroxybutyrate functions as an HDAC inhibitor within MuSCs leading to acetylation and activation of an HDAC1 target protein p53. Finally, we demonstrate that p53 activation contributes to the deep quiescence and enhanced resilience observed during fasting.
2022-09-28 | GSE184821 | 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:Skeletal muscle possesses remarkable regenerative ability owing to the resident muscle stem cells (MuSCs). A prominent feature of quiescent MuSCs is a high content of heterochromatin. However, little is known about the mechanisms by which heterochromatin is maintained in MuSCs. We found that the mammalian Hairless (Hr) gene is expressed in quiescent MuSCs. Using a mouse model in which Hr can be specifically ablated in MuSCs, we demonstrate that Hr expression is critical for MuSC function and muscle regeneration. We show that Hr is a histone demethylase antagonist that preserves Histone 3 Lysine 9 trimethylation (H3K9me3) and maintains heterochromatin structure. Loss of Hr results in reduced H3K9me3 levels, reduced heterochromatin, increased susceptibility of MuSCs to genotoxic stress, and the accumulation of DNA damage. Our study not only elucidates the molecular mechanism by which Hr regulates histone demethylases, but also demonstrates the importance of heterochromatin maintenance in stem cell function.
2021-09-09 | GSE132220 | GEO
Project description:Skeletal muscle possesses remarkable regenerative ability owing to the resident muscle stem cells (MuSCs). A prominent feature of quiescent MuSCs is a high content of heterochromatin. However, little is known about the mechanisms by which heterochromatin is maintained in MuSCs. We found that the mammalian Hairless (Hr) gene is expressed in quiescent MuSCs. Using a mouse model in which Hr can be specifically ablated in MuSCs, we demonstrate that Hr expression is critical for MuSC function and muscle regeneration. We show that Hr is a histone demethylase antagonist that preserves Histone 3 Lysine 9 trimethylation (H3K9me3) and maintains heterochromatin structure. Loss of Hr results in reduced H3K9me3 levels, reduced heterochromatin, increased susceptibility of MuSCs to genotoxic stress, and the accumulation of DNA damage. Our study not only elucidates the molecular mechanism by which Hr regulates histone demethylases, but also demonstrates the importance of heterochromatin maintenance in stem cell function.
2021-09-09 | GSE132189 | GEO