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Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice

Abstract

Age-related changes in the niche have long been postulated to impair the function of somatic stem cells. Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs). Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers. By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche. Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism.

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Figure 1: Aging affects FN levels during skeletal muscle regeneration.
Figure 2: Fibronectin is a preferred adhesion substrate for mouse and human muscle progenitors.
Figure 3: MuSC aging pathways are modulated by fibronectin.
Figure 4: Impaired FN-mediated adhesion signaling in aged MuSCs.
Figure 5: Exposure to FN rescues adhesion signaling in aged MSCs.
Figure 6: Fibronectin treatment restores the regenerative capacity of aged muscles.

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Acknowledgements

We thank J. Ritchie for help with mouse husbandry. We are grateful to the NIHS community for fruitful discussions and support, in particular to the Aging and Stem Cells groups, and to E. Rolland and E. Baetge. We thank C. Poser for excellent technical assistance. ROSA26–CreERT2 mice were provided by F. Stewart (Technische Universität Dresden, Germany) as a kind gift to M.A.R. J.V.M. and M.J.J. were supported by a grant from the German Research Foundation (DFG) (grant MA–3975/2–1). M.A.R. holds the Canada Research Chair in Molecular Genetics and is supported by a grant from the Government of the Ontario Ministry of Research and Innovation (MRI) (grant ORF–RE05–084). M.R. and C.M.F. are supported by the National Institutes of Health grants (grants HD075345 and AR060042). C.F.B. is supported by the Fondation Suisse de Recherche sur les Maladies Musculaires (FSRMM).

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M.J.J., N.H., C.P.-C., M.R., S.K., M.S., L. Li, S.M., U.L., F.S., N.A.D., A.P., C.-M.F. and J.v.M., designed and conducted experiments, and analyzed results; E.M. and F.R. performed data analysis; G.J. provided support with high-content image acquisition and analysis; M.A.R. provided critical reagents, edited the manuscript and helped with data interpretation; R.F. provided critical reagents; D.H.W. helped with data acquisition and analysis; P.S. and P.D. helped with experimental design, data interpretation and editing of the manuscript; and L. Lukjanenko, J.N.F. and C.F.B. designed and conducted experiments, analyzed results and wrote the manuscript.

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Correspondence to Jerome N Feige or C Florian Bentzinger.

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L. Lukjanenko, N.H., C.P.-C., E.M., S.K., G.J., S.M., F.R., U.L., F.S., A.P., P.S., P.D., J.N.F. and C.F.B. are employees of the Nestlé Institute of Health Sciences S.A., Switzerland.

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Lukjanenko, L., Jung, M., Hegde, N. et al. Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice. Nat Med 22, 897–905 (2016). https://doi.org/10.1038/nm.4126

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