GLI3 regulates muscle stem cell entry into GAlert and self-renewal

Brun, Caroline E.; Sincennes, Marie-Claude; Lin, Alexander Y.; Hall, Derek T; Jarassier, William; Feige, Peter; Grand, Fabien Le; Rudnicki, Michael A.

doi:10.1038/s41467-022-31695-5

Cited by 28 publications

(38 citation statements)

References 67 publications

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“…We found that FAPs are the main cell population that display active Hh signaling followed by MuSCs (Fig 1c). As only ciliated cells can respond to Hh signaling, these results fit with our 8 and other previous findings 40,43,44,48,49 that FAPs and MuSCs are the only ciliated cell populations in muscle with FAPs making up the highest proportion of ciliated cells. Thus, our data reveal that an acute muscle injury activates Hh signaling within ciliated FAPs and MuSCs through induction of Dhh (Fig 1d).…”

supporting

confidence: 93%

“…How does DHH control myofiber regeneration? The two main cell populations that carry a primary cilium, and thereby can respond to DHH, are FAPs and MuSCs 43, 48, 65, 66, 67 . Fittingly, we found that both cell populations display an active Hh signature indicating that they sense DHH.…”

Section: Discussionmentioning

confidence: 99%

“…Fittingly, we found that both cell populations display an active Hh signature indicating that they sense DHH. While our understanding of the role of cilia and ciliary Hh signaling in MuSCs is still evolving, recent findings demonstrate that MuSCs cilia control the balance between quiescence, self-renewal and proliferation 43, 44, 48, 65, 67 . Thus, Hh signaling may directly influence the myogenic compartment explaining why loss of Dhh results in impaired muscle regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…How does ectopic Hh activation impact regeneration-induced myogenesis? As FAPs and MuSCs possess a primary cilium 43,48,49,65,66,67 , both cell types are capable of responding to either DHH or SAG. Therefore, Hh activation could impair myogenesis via a direct influence on MuSCs or indirectly through FAPs.…”

Section: Hh Activation Within Faps Blocks Imat and Indirectly Impairs...mentioning

confidence: 99%

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Hedgehog signaling via its ligand DHH acts as cell fate determinant during skeletal muscle regeneration

Norris

Johnson

Zhou

et al. 2022

Preprint

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Failed tissue regeneration often results in fatty fibrosis, the replacement of healthy cells with fibrotic scar and fat tissue. However, the causative signals remain largely unknown. Here, we describe how the Hedgehog (Hh) signaling pathway controls the fate of fibro/adipogenic progenitors (FAPs), the cellular origin of fatty fibrosis. Using conditional mutagenesis and pharmacological Hh modulators, we identify DHH as the main ligand through which Hh restricts intramuscular fat (IMAT) formation and promotes muscle regeneration. In contrast, conditionally activating Hh specifically in FAPs skews them from an adipogenic towards a fibrogenic fate resulting in massive fibrotic scar tissue. Surprisingly, FAP-specific Hh activation also impairs myoblast differentiation leading to muscle regeneration defects. Together, our data reveal novel post-developmental functions of Hh signaling in balancing tissue regeneration and fatty fibrosis. Moreover, they provide the exciting possibility that mis-regulation of the Hh pathway with age and disease could be a major driver of pathological IMAT formation, thereby representing an attractive therapeutic target.

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supporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Hh Activation Within Faps Blocks Imat and Indirectly Impairs...mentioning

confidence: 99%

See 2 more Smart Citations

Hedgehog signaling via its ligand DHH acts as cell fate determinant during skeletal muscle regeneration

Norris

Johnson

Zhou

et al. 2022

Preprint

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“…Moreover, treatment of MuSCs with TubA improved engraftment potential upon transplantation ( Arjona et al, 2022 ). In addition, data from our group demonstrated that primary cilia-mediated regulation of GLI3 transcription factor plays an important role in keeping the satellite cells in their dormant G0 state and inhibiting their activation ( Brun et al, 2022 ).…”

Section: Transplantation-based Approach To Assess Satellite Cell Func...mentioning

confidence: 99%

Transplantation to study satellite cell heterogeneity in skeletal muscle

Hekmatnejad

Rudnicki

2022

Front. Cell Dev. Biol.

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Skeletal muscle has a remarkable capacity to regenerate throughout life, which is mediated by its resident muscle stem cells, also called satellite cells. Satellite cells, located periphery to the muscle fibers and underneath the basal lamina, are an indispensable cellular source for muscle regeneration. Satellite cell transplantation into regenerating muscle contributes robustly to muscle repair, thereby indicating that satellite cells indeed function as adult muscle stem cells. Moreover, satellite cells are a heterogenous population in adult tissue, with subpopulations that can be distinguished based on gene expression, cell-cycle progression, ability to self-renew, and bi-potential ability. Transplantation assays provide a powerful tool to better understand satellite cell function in vivo enabling the separation of functionally distinct satellite cell subpopulations. In this review, we focus on transplantation strategies to explore satellite cells’ functional heterogeneity, approaches targeting the recipient tissue to improve transplantation efficiency, and common strategies to monitor the behaviour of the transplanted cells. Lastly, we discuss some recent approaches to overcome challenges to enhance the transplantation potential of muscle stem cells.

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Muscle stem cells get a new look: Dynamic cellular projections as sensors of the stem cell niche

Krauss

Kann

2023

BioEssays

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Cellular mechanisms whereby quiescent stem cells sense tissue injury and transition to an activated state are largely unknown. Quiescent skeletal muscle stem cells (MuSCs, also called satellite cells) have elaborate, heterogeneous projections that rapidly retract in response to muscle injury. They may therefore act as direct sensors of their niche environment. Retraction is driven by a Rac‐to‐Rho GTPase activity switch that promotes downstream MuSC activation events. These and other observations lead to several hypotheses: (1) projections are morphologically dynamic at quiescence, providing a surveillance function for muscle damage; (2) quiescent projection dynamics are regulated by the relative balance of Rac and Rho activities promoted by niche‐derived cues; (3) projections, particularly their associated filopodia, sense tissue damage via changes to the biomechanical properties of the niche and/or detection of signaling cues released by damaged myofibers; and (4) the dynamic nature of projections results in a population of MuSCs with heterogeneous functional properties. These concepts may extend to other types of quiescent stem cells, as well as prove useful in translational research settings.

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GLI3 regulates muscle stem cell entry into GAlert and self-renewal

Cited by 28 publications

References 67 publications

Hedgehog signaling via its ligand DHH acts as cell fate determinant during skeletal muscle regeneration

Hedgehog signaling via its ligand DHH acts as cell fate determinant during skeletal muscle regeneration

Transplantation to study satellite cell heterogeneity in skeletal muscle

Muscle stem cells get a new look: Dynamic cellular projections as sensors of the stem cell niche

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