The aged niche disrupts muscle stem cell quiescence

• Published in: Nature (London) Vol. 490; no. 7420; pp. 355 - 360
• Main Authors: Chakkalakal, Joe V., Jones, Kieran M., Basson, M. Albert, Brack, Andrew S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.10.2012; Nature Publishing Group
• Subjects: 631/136/532/2439; 631/532/2139; 631/80/86; Adaptor Proteins, Signal Transducing; Aging; Aging - physiology; Animals; Apoptosis; Biological and medical sciences; Cell Count; Cell Cycle; Cell Differentiation; Cellular Senescence; Cellular signal transduction; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Drinking water; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - metabolism; Fibroblast growth factors; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Homeostasis; Humanities and Social Sciences; Ligands; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; multidisciplinary; Muscle Cells - cytology; Muscle, Skeletal - cytology; Muscular system; Musculoskeletal system; PAX7 Transcription Factor - metabolism; Phosphoproteins - metabolism; Physiological aspects; Proteins; Satellite Cells, Skeletal Muscle - cytology; Satellite Cells, Skeletal Muscle - metabolism; Satellite Cells, Skeletal Muscle - transplantation; Science; Science (multidisciplinary); Signal Transduction; Stem Cell Niche - physiology; Stem cells; Striated muscle. Tendons; Time Factors; Vertebrates: osteoarticular system, musculoskeletal system; United States; United Kingdom; Vertebrata; Mammalia; Mouse; Animal; Stem cell; Ageing; Rodentia; Homeostasis; Muscle; Satellite cell; Quiescence
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11438

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. The expression of fibroblast growth factor in aged muscle fibre, the muscle stem cell niche, is shown to cause satellite cells to lose the capacity for self-renewal, and is thus an age-dependent change that directly influences stem cell quiescence and function. Stem-cell niche less stable with age The efficiency of stem-cell maintenance declines with age, but it is not clear whether the stem-cell niche itself plays a part in this decline. Here, Andrew Brack and colleagues report that as mice age, the skeletal-muscle niche becomes more mitogenic — meaning more cells undergo mitosis and differentiation — and less capable of maintaining the quiescence of the skeletal-muscle stem cells. This results in the loss of capacity for stem-cell self-renewal. The protein FGF2 is a key mitogenic factor in the aged niche, although a small number of muscle stem cells express SPRY1, an inhibitor of FGF signalling, and maintain some quiescence in aged skeletal-muscle fibres.