HEXIM1 controls satellite cell expansion after injury to regulate skeletal muscle regeneration

Hong, Peng; Chen, Kang; Huang, Bihui; Liu, Min; Cui, Miao; Rozenberg, Inna; Chaqour, Brahim; Pan, Xiaoyue; Barton, Elisabeth R.; Jiang, Xian Cheng; Siddiqui, M.A.Q.

doi:10.1172/jci62818

Cited by 12 publications

(11 citation statements)

References 58 publications

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“…In contrast to myoblast transplantation studies (25)(26)(27), our data reveal that the effect of transplanted PLX-PAD cells is not based on differentiation but rather on trophic and immunomodulatory support of the endogenous regeneration. This finding is consistent with recent studies on tendon healing demonstrating the decisive role of early trophic factor delivery to the site of injury.…”

Section: Discussioncontrasting

confidence: 97%

Placental-expanded, mesenchymal cells improve muscle function following hip arthroplasty

Winkler

Perka

Roth

et al. 2018

Preprint

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Background:No regenerative approach has thus far been shown to be effective in skeletal muscle injuries, despite high frequency and associated functional deficits. We sought to address surgical trauma related muscle injuries using local intraoperative application of allogeneic placenta-derived, mesenchymal-like adherent cells (PLX-PAD), using hip arthroplasty as a standardized injury model, because of the high regenerative and immunomodulatory potency of this cell type. Methods:Our pilot phase I/IIa study was prospective, randomized, double blind and placebocontrolled. Twenty patients undergoing hip arthroplasty via a direct lateral approach were injected with 3.0×10 8 or 1.5×10 8 PLX-PAD or a placebo into the gluteus medius muscle. Results:We did not observe any relevant PLX-PAD-related adverse events at the 2-year follow-up. Improved gluteus medius strength was noted as early as week 6 in the treatmentgroups. Surprisingly, until week 26 the low-dose outperformed the high-dose group and reached significantly improved strength compared to placebo, mirrored by an increase in muscle volume.Histology indicated accelerated healing after cell therapy. Biomarker studies revealed that lowdose treatment reduced the surgery-related immunological stress reaction more than high-dose.Signs of late-onset immune reactivity after high-dose treatment corresponded to reduced functional improvement. Conclusion:Allogeneic PLX-PAD therapy improved strength and volume of injured skeletal muscle with a reasonable safety profile. Outcomes could be positively correlated with the modulation of early postoperative stress-related immunological reactions.

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Section: Discussioncontrasting

confidence: 97%

Placental-expanded, mesenchymal cells improve muscle function following hip arthroplasty

Winkler

Perka

Roth

et al. 2018

Preprint

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“…We also observed increased proliferation and apoptosis of satellite cells in regenerating KPNA1 KO muscle as in uninjured muscle. Increased proliferation of satellite cells in regenerating muscles has been previously noted with the knockout of Notch signaling‐related proteins , Hexamethylene Bis‐Acetamide Inducible 1 and Mitogen‐Activated Protein kinase phosphatase 5 resulting in enhanced hypertrophy of regenerated myofibers. We noted enhanced myofiber size in the early phases of regeneration in KPNA1 KO muscles but this was not maintained at late phases likely due to apoptotic satellite cells.…”

Section: Discussionmentioning

confidence: 74%

Karyopherin Alpha 1 Regulates Satellite Cell Proliferation and Survival by Modulating Nuclear Import

Choo¹,

Cutler

Rother

et al. 2016

Stem Cells

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Satellite cells are stem cells with an essential role in skeletal muscle repair. Precise regulation of gene expression is critical for proper satellite cell quiescence, proliferation, differentiation and self -renewal. Nuclear proteins required for gene expression are dependent on the nucleocytoplasmic transport machinery to access to nucleus, however little is known about regulation of nuclear transport in satellite cells. The best characterized nuclear import pathway is classical nuclear import which depends on a classical nuclear localization signal (cNLS) in a cargo protein and the heterodimeric import receptors, karyopherin alpha (KPNA) and beta (KPNB). Multiple KPNA1 paralogs exist and can differ in importing specific cNLS proteins required for cell differentiation and function. We show that transcripts for six Kpna paralogs underwent distinct changes in mouse satellite cells during muscle regeneration accompanied by changes in cNLS proteins in nuclei. Depletion of KPNA1, the most dramatically altered KPNA, caused satellite cells in uninjured muscle to prematurely activate, proliferate and undergo apoptosis leading to satellite cell exhaustion with age. Increased proliferation of satellite cells led to enhanced muscle regeneration at early stages of regeneration. In addition, we observed impaired nuclear localization of two key KPNA1 cargo proteins: p27, a cyclin-dependent kinase inhibitor associated with cell cycle control and lymphoid enhancer factor 1, a critical co-transcription factor for β-catenin. These results indicate that regulated nuclear import of proteins by KPNA1 is critical for satellite cell proliferation and survival and establish classical nuclear import as a novel regulatory mechanism for controlling satellite cell fate.

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“…Release of stalled polymerase is brought about by coordinated regulation of P-TEFb mediated by SEC, Brd4, Hexim1 (Lu et al, 2016;Puri et al, 2015). Hexim1 haplo-deficiency in mice Gala et al,Pol II pausing in G 0 24 increases satellite cell activity and muscle regeneration, highlighting a role in self-renewal (Galatioto et al, 2010;Hong et al, 2012). While Hexim1 knockdown did not affect the timing of cell cycle re-entry, an effect in quiescence cannot be ruled out and the repression of some G 0stalled genes warrants further investigation.…”

Section: The Sec Component Aff4 Regulates G 0 -Stalled Genes To Contrmentioning

confidence: 99%

RNA polymerase II pausing regulates a quiescence-dependent transcriptional program, priming cells for cell cycle reentry

Gala

Saha

Venugopal

et al. 2018

Preprint

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Adult stem cells persist in mammalian tissues by entering a state of reversible arrest or quiescence associated with low transcription. Using cultured myoblasts and primary muscle stem cells, we show that RNA synthesis is strongly repressed in G 0, returning within minutes of activation. We investigate the underlying mechanism and reveal a role for promoter-proximal RNAPol II pausing: by mapping global Pol II occupancy using ChIP-seq, in conjunction with RNA-seq to identify repressed transcriptional networks unique to G 0 . Strikingly, Pol II pausing is enhanced in G 0 on genes encoding regulators of RNA biogenesis (Ncl, Rps24, Ctdp1), and release of pausing is critical for cell cycle re-entry. Finally, we uncover a novel, unexpected repressive role of the super-elongation complex component Aff4 in G 0 -specific stalling. We propose a model wherein Pol II pausing restrains transcription to maintain G 0 , preconfigures gene networks required for the G 0 -G 1 transition, and sets the timing of their transcriptional activation.

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HEXIM1 controls satellite cell expansion after injury to regulate skeletal muscle regeneration

Cited by 12 publications

References 58 publications

Placental-expanded, mesenchymal cells improve muscle function following hip arthroplasty

Placental-expanded, mesenchymal cells improve muscle function following hip arthroplasty

Karyopherin Alpha 1 Regulates Satellite Cell Proliferation and Survival by Modulating Nuclear Import

RNA polymerase II pausing regulates a quiescence-dependent transcriptional program, priming cells for cell cycle reentry

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