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Researchers Discover how Notch Duo Coordinate Muscle Stem Cell Regulation

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Review of “Notch1 and Notch2 Coordinately Regulate Stem Cell Function in the Quiescent and Activated States of Muscle Satellite Cells” from STEM CELLS by Stuart P. Atkinson

Muscle stem cells usually lie in a resting “quiescent” state until a stimulus (such as muscle injury) kicks them back into proliferative life to foster the growth of new muscle tissue before they return to their quiescent state. This on-off relationship requires tight coordination, but we only have limited data on the factors at play and what roles they carry out.

This knowledge gap prompted researchers from the laboratory of Yusuke Ono (Nagasaki University, Japan) to assess a potential role for the development and regeneration-associated Notch signaling pathway [1, 2] in muscle stem cell regulation. Their new STEM CELLS study now describes how the Notch1 and Notch2 duo act together to maintain quiescence and regulate stem-cell-fate decision in muscle stem cells of adult mice [3].

Fujimaki et al. began their study by generating muscle stem cell-specific conditional Notch knockout (KO) mice to allow the authors to study the consequences of the loss of one or both Notch proteins in adult skeletal muscle. While Notch1 KO barely affected quiescent muscle stem cell number in non-injured mice, Notch2 KO and double KO (DKO) muscles demonstrated severely reduced numbers (more notable for DKO mice), suggesting a degree of functional compensation between Notch1 and Notch2. Following injury (cardiotoxin injection), the weight of regenerating muscle reduced and levels of fibrosis increased in all three KO mice; however, DKO mice displayed the most severe phenotype, overall suggesting that muscle regeneration after muscle injury in vivo requires the Notch1 and Notch2 duo. 

Similar studies in activated muscle stem cells demonstrated that Notch1 and Notch2 promoted proliferation by inhibiting differentiation towards satellite cell-derived myoblasts and therefore play an additional essential role in muscle stem cell self-renewal.

This exciting new study establishes critical roles for Notch1 and Notch2 in quiescent and activated muscle stem cells, information that the authors hope will contribute towards advances in muscle-targeted regenerative medicine and the treatment of diseases such as age-related sarcopenia and Duchenne muscular dystrophy.

For more on the factors and mechanisms that coordinate muscle stem cell regulation, stay tuned to the Stem Cells Portal!

References

  1. Koch U, Lehal R, and Radtke F, Stem cells living with a Notch. Development 2013;140:689-704.
  2. Mourikis P and Tajbakhsh S, Distinct contextual roles for Notch signalling in skeletal muscle stem cells. BMC Developmental Biology 2014;14:2.
  3. Fujimaki S, Seko D, Kitajima Y, et al., Notch1 and Notch2 Coordinately Regulate Stem Cell Function in the Quiescent and Activated States of Muscle Satellite Cells. STEM CELLS 2018;36:278-285.