Notch1 and Notch2 Coordinately Regulate Stem Cell Function in the Quiescent and Activated States of Muscle Satellite Cells

Fujimaki, Shin; Seko, Daiki; Kitajima, Yasuo; Yoshioka, Kiyoshi; Tsuchiya, Yoshifumi; Masuda, Shinji; Ono, Yusuke

doi:10.1002/stem.2743

Cited by 86 publications

(66 citation statements)

References 61 publications

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“…As mentioned, the canonical Notch pathway is essential for maintaining MuSCs in a quiescent and undifferentiated state; in the absence of Rbp-J, MuSC numbers decline quickly, and the myogenic differentiation factors MyoD and myogenin are upregulated (Bjornson et al, 2012;Mourikis et al, 2012). Double conditional mutagenesis of Notch1 and Notch2 results in similar phenotypes to observations in Rbp-J-depleted MuSCs, indicating that the canonical Notch1/2-Rbp-J axis is a key pathway for adult MuSCs maintenance (Fujimaki et al, 2018). However, similar to the myogenic cell line, the downstream molecules for maintaining adult MuSCs remain to be elucidated.…”

Section: Introductionmentioning

confidence: 58%

“…We reported previously that in Hey1 and HeyL double knockout (dKO) mice, but not in Hey1 or HeyL single KO mice, the generation of quiescent MuSCs was impaired as a consequence of an increase in MyoD and myogenin expression (Fukada et al, 2011). This resembles the phenotypes of Rbp-J conditional KO (cKO) and Notch1/2 double cKO mice (Bjornson et al, 2012;Fujimaki et al, 2018;Mourikis et al, 2012). In this study, genetically Hey1/HeyL-null mice were analyzed.…”

Section: Introductionmentioning

confidence: 83%

“…Canonical Notch signaling is an essential pathway for maintaining the undifferentiated state of MuSCs (Bjornson et al, 2012;Fujimaki et al, 2018;Mizuno et al, 2015;Mourikis et al, 2012). However, the downstream effectors exerting the anti-myogenic effects have not been identified.…”

Section: Discussionmentioning

confidence: 99%

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Cell-autonomous and redundant roles of Hey1 and HeyL in muscle stem cells: HeyL requires Hes1 to bind diverse DNA sites

et al. 2019

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The undifferentiated state of muscle stem (satellite) cells (MuSCs) is maintained by the canonical Notch pathway. Although three bHLH transcriptional factors, Hey1, HeyL and Hes1, are considered to be potential effectors of the Notch pathway exerting anti-myogenic effects, neither HeyL nor Hes1 inhibits myogenic differentiation of myogenic cell lines. Furthermore, whether these factors work redundantly or cooperatively is unknown. Here, we showed cellautonomous functions of Hey1 and HeyL in MuSCs using conditional and genetic null mice. Analysis of cultured MuSCs revealed antimyogenic activity of both HeyL and Hes1. We found that HeyL forms heterodimeric complexes with Hes1 in living cells. Moreover, our ChIP-seq experiments demonstrated that, compared with HeyL alone, the HeyL-Hes1 heterodimer binds with high affinity to specific sites in the chromatin, including the binding sites of Hey1. Finally, analyses of myogenin promoter activity showed that HeyL and Hes1 act synergistically to suppress myogenic differentiation. Collectively, these results suggest that HeyL and Hey1 function redundantly in MuSCs, and that HeyL requires Hes1 for effective DNA binding and biological activity.

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Section: Introductionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 83%

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Cell-autonomous and redundant roles of Hey1 and HeyL in muscle stem cells: HeyL requires Hes1 to bind diverse DNA sites

et al. 2019

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“…Notch 1, 2, and 3 are expressed in quiescent SCs, while muscle fibers are the major source of Notch ligands, such as Delta and Jagged [11][12][13]. Notch activation prevents myogenic differentiation and promotes satellite cell self-renewal, by upregulating Pax7 and inhibiting MyoD [14,15]. In the absence of Notch, SCs undergo accelerated terminal differentiation without self-renewal, resulting in muscle stem cell pool depletion [16].…”

Section: Introductionmentioning

confidence: 99%

Lack of PKCθ Promotes Regenerative Ability of Muscle Stem Cells in Chronic Muscle Injury

Fiore

Benedetti

Sandonà

et al. 2020

IJMS

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Duchenne muscular dystrophy (DMD) is a genetic disease characterized by muscle wasting and chronic inflammation, leading to impaired satellite cells (SCs) function and exhaustion of their regenerative capacity. We previously showed that lack of PKCθ in mdx mice, a mouse model of DMD, reduces muscle wasting and inflammation, and improves muscle regeneration and performance at early stages of the disease. In this study, we show that muscle regeneration is boosted, and fibrosis reduced in mdxθ−/− mice, even at advanced stages of the disease. This phenotype was associated with a higher number of Pax7 positive cells in mdxθ−/− muscle compared with mdx muscle, during the progression of the disease. Moreover, the expression level of Pax7 and Notch1, the pivotal regulators of SCs self-renewal, were upregulated in SCs isolated from mdxθ−/− muscle compared with mdx derived SCs. Likewise, the expression of the Notch ligands Delta1 and Jagged1 was higher in mdxθ−/− muscle compared with mdx. The expression level of Delta1 and Jagged1 was also higher in PKCθ−/− muscle compared with WT muscle following acute injury. In addition, lack of PKCθ prolonged the survival and sustained the differentiation of transplanted myogenic progenitors. Overall, our results suggest that lack of PKCθ promotes muscle repair in dystrophic mice, supporting stem cells survival and maintenance through increased Delta-Notch signaling.

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“…The ability to investigate the mechanisms regulating self-renewal depends on the ability to study cells as they undergo cell fate decisions. These functions have typically been interrogated in myogenic cells propagated on artificial 2D substrates in vitro or single myofiber explants ex vivo (Fujimaki et al 2018;Kuang et al 2007;Zammit 2008). However, myogenic cells 3 under these conditions do not fully recapitulate innate satellite cell behavior, nor the complex environment of muscle tissue and their utility as models of satellite cell fate decision and muscle regeneration is limited (Webster et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity of satellite cells implicates DELTA1/NOTCH2 signaling in self-renewal

Yartseva¹,

Goldstein²,

Rodman³

et al. 2019

Preprint

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How satellite cells and their progenitors balance differentiation and self-renewal to achieve sustainable tissue regeneration is not well understood. A major roadblock to understanding satellite cell fate decisions has been the difficulty to study this process in vivo. By visualizing expression dynamics of myogenic transcription factors during early regeneration in vivo, we identified the time point at which cells undergo decisions to differentiate or self-renew.Single-cell RNA sequencing revealed heterogeneity of satellite cells during both muscle homeostasis and regeneration, including a subpopulation enriched in Notch2 receptor expression. Furthermore, we reveal that differentiating cells express the Dll1 ligand. Using antagonistic antibodies we demonstrate that the DLL1 and NOTCH2 signaling pair is required for satellite cell self-renewal. Thus, differentiating cells provide the self-renewing signal during regeneration, enabling proportional regeneration in response to injury while maintaining the satellite cell pool. These findings have implications for therapeutic control of muscle regeneration.

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Notch1 and Notch2 Coordinately Regulate Stem Cell Function in the Quiescent and Activated States of Muscle Satellite Cells

Cited by 86 publications

References 61 publications

Cell-autonomous and redundant roles of Hey1 and HeyL in muscle stem cells: HeyL requires Hes1 to bind diverse DNA sites

Cell-autonomous and redundant roles of Hey1 and HeyL in muscle stem cells: HeyL requires Hes1 to bind diverse DNA sites

Lack of PKCθ Promotes Regenerative Ability of Muscle Stem Cells in Chronic Muscle Injury

Heterogeneity of satellite cells implicates DELTA1/NOTCH2 signaling in self-renewal

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