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The aged niche disrupts muscle stem cell quiescence

Abstract

The niche is a conserved regulator of stem cell quiescence and function. During ageing, stem cell function declines. To what extent and by what means age-related changes within the niche contribute to this phenomenon are unknown. Here we demonstrate that the aged muscle stem cell niche, the muscle fibre, expresses Fgf2 under homeostatic conditions, driving a subset of satellite cells to break quiescence and lose their self-renewing capacity. We show in mice that relatively dormant aged satellite cells robustly express sprouty 1 (Spry1), an inhibitor of fibroblast growth factor (FGF) signalling. Increasing FGF signalling in aged satellite cells under homeostatic conditions by removing Spry1 results in the loss of quiescence, satellite cell depletion and diminished regenerative capacity. Conversely, reducing niche-derived FGF activity through inhibition of Fgfr1 signalling or overexpression of Spry1 in satellite cells prevents their depletion. These experiments identify an age-dependent change in the stem cell niche that directly influences stem cell quiescence and function.

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Figure 1: Aged satellite cells cycle more frequently during homeostasis.
Figure 2: Preservation of quiescence protects satellite cell function.
Figure 3: Fgf2 is an aged-niche-derived factor that induces satellite cells to cycle.
Figure 4: Aged satellite cells are sensitive to acute changes in FGF signalling.
Figure 5: Longer-term changes in FGF signalling drive satellite cell depletion.

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Acknowledgements

We thank H. Hock, K. Hochedlinger and R. Friesel for the generous provision of reagents, and G. Estrada for technical assistance. We are also grateful to L. Prickett-Rice, K. Folz-Donahue and M. Weglarz for cell sorting. This work was supported by MGH start-up funds, Harvard Stem Cell Institute grants and NIH grants (R01 AR060868, R01 AR061002) (A.S.B.); a Wellcome Trust grant (WT091475) (M.A.B.); and an MGH ECOR Postdoctoral Fellow Award (J.V.C.) and a BBSRC Doctoral Training Award (BB/F017626/1) (K.M.J.).

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J.V.C. designed and performed experiments, analysed data, interpreted results and wrote the manuscript. K.M.J. performed experiments, analysed data and edited the manuscript. M.A.B. conceived the project, designed experiments, interpreted results, and edited the manuscript. A.S.B. conceived the project, designed experiments, interpreted results, and wrote the manuscript.

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Correspondence to Andrew S. Brack.

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The authors declare no competing financial interests.

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Chakkalakal, J., Jones, K., Basson, M. et al. The aged niche disrupts muscle stem cell quiescence. Nature 490, 355–360 (2012). https://doi.org/10.1038/nature11438

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