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Setd7 Inhibition: The Way Forward for MuSC-based Therapies for Muscular Dystrophy?

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Review of “Inhibition of Methyltransferase Setd7 Allows the In Vitro Expansion of Myogenic Stem Cells with Improved Therapeutic Potential” from Cell Stem Cell by Stuart P. Atkinson

The in vitro expansion of muscle stem cells (MuSCs), also known as satellite cells, may provide a potent means to treat a wide range of muscle-related diseases such as sarcopenia and muscular dystrophy. However, finding the proper in vitro conditions to cultivate large numbers of engraftable and functional cells remains a significant problem [1].

A recent study from the laboratories of Thomas A. Rando (Stanford University, California, USA) and Fabio M. Rossi (University of British Columbia, Canada) now provides evidence that modulation of Setd7, a lysine methyltransferase previously indicated to play a role in myogenesis [2], can enhance the therapeutic value of in vitro cultured MuSCs [3] and may represent the way forward for MuSC-based therapies.  

Judson et al. began their investigation in quiescent MuSCs, where they discovered an absence of Setd7 expression. However, Setd7 expression increased with the progression of myogenesis in vitro indicating the potential importance of this event for skeletal muscle development and regeneration in vivo. Deletion of Setd7 in MuSCs revealed a block in myogenic differentiation and while the loss of Setd7 function in vivo did permit muscle development in mice, the lack of this methyltransferase impaired regenerative responses following acute injury.

However, the authors found no evidence for a role of Setd7 in histone methylation or as a partner of MyoD in MuSCs and instead, they discovered that Setd7 interacted with -catenin and modulated its methylation status to promote nuclear translocation and the transcription of Wnt-responsive myogenic genes. Interestingly, treatment with a selective and potent small-molecule inhibitor of Setd7 activity (PFI-2) [4] impaired -catenin translocation and myogenic gene expression, and thereby promoted the maintenance of MuSCs in an immature state. Excitingly, the in vitro expansion of MuSC cultures in the presence of PFI-2 increased the yield and maintained the self-renewal capacity of MuSCs, and following transplantation into injured tibialis anterior muscles of muscular dystrophy model mice, boosted MuSC engraftment and overall therapeutic efficacy.

The authors note the significant translational implications of this new study; Setd7 inhibition may improve outcomes of stem cell therapies for disorders such as muscular dystrophy [5] and allow the massive in vitro expansion of MuSCs without significantly impairing engraftment and self-renewal [6]. This latter point will permit a more in-depth analysis of MuSC biology, genetic modification/correction of MuSCs, drug screenings, and, importantly, the development of new and improved MuSC-based therapies for a wide range of muscle diseases.

To discover the next steps on the way forward for this exciting breakthrough for muscle stem cell research, stay tuned to the Stem Cells Portal!

References

  1. Rinaldi F and Perlingeiro RC, Stem cells for skeletal muscle regeneration: therapeutic potential and roadblocks. Transl Res 2014;163:409-17.
  2. Tao Y, Neppl RL, Huang ZP, et al., The histone methyltransferase Set7/9 promotes myoblast differentiation and myofibril assembly. J Cell Biol 2011;194:551-65.
  3. Judson RN, Quarta M, Oudhoff MJ, et al., Inhibition of Methyltransferase Setd7 Allows the In Vitro Expansion of Myogenic Stem Cells with Improved Therapeutic Potential. Cell Stem Cell;22:177-190.e7.
  4. Barsyte-Lovejoy D, Li F, Oudhoff MJ, et al., PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells. Proceedings of the National Academy of Sciences 2014;111:12853-12858.
  5. Wilschut KJ, Ling VB, and Bernstein HS, Concise Review: Stem Cell Therapy for Muscular Dystrophies. STEM CELLS Translational Medicine 2012;1:833-842.
  6. Montarras D, Morgan J, Collins C, et al., Direct Isolation of Satellite Cells for Skeletal Muscle Regeneration. Science 2005;309:2064-2067.