Division-Independent Differentiation of Muscle Stem Cells During a Growth Stimulus
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE235102 | GEO | 2023/12/06
REPOSITORIES: GEO
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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.
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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.
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Project description:Stem cells reside in specialized niches that play a critical role in modulating their fate. It remains unknown how MuSC adapt to the modified milieu to mediate muscle repair. Here, we show that the epigenetic enzyme JMJD3 coordinates MuSC adaptation to the regenerative niche in a non-cell autonomous manner where it modifies their extracellular matrix to integrate signaling that stimulates exit of quiescence. Genomics and transcriptomics approaches identified the hyaluronic acid (HA) synthesis enzyme Has2 as a key JMJD3 target gene that allows MuSCs to integrate signals from the regenerative niche.
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Project description:Stem cells reside in specialized niches that play a critical role in modulating their fate. It remains unknown how MuSC adapt to the modified milieu to mediate muscle repair. Here, we show that the epigenetic enzyme JMJD3 coordinates MuSC adaptation to the regenerative niche in a non-cell autonomous manner where it modifies their extracellular matrix to integrate signaling that stimulates exit of quiescence. Genomics and transcriptomics approaches identified the hyaluronic acid (HA) synthesis enzyme Has2 as a key JMJD3 target gene that allows MuSCs to integrate signals from the regenerative niche.
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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.
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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.
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Project description:Muscle stem cells (MuSCs) are required for muscle regeneration. In resting muscles, MuSCs are kept in quiescence. After injury, MuSCs undergo rapid activation, proliferation and differentiation to repair damaged muscles. Age-associated impairments in stem cell functions correlate with a decline in somatic tissue regeneration capacity during aging. However, the mechanisms underlying the molecular regulation of adult stem cell aging remain elusive. Here, we obtained quisecent MuSCs from young, old, geriatric mice for high resolution mass spectrometry Bruker timsTOF Pro. By comparison of young proteome to old MuSCs proteome or geriatric MuSC proteome, we identified the pathways that are differentially during aging.
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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.
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