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Rejuvenation of the muscle stem cell population restores strength to injured aged muscles

Abstract

The elderly often suffer from progressive muscle weakness and regenerative failure. We demonstrate that muscle regeneration is impaired with aging owing in part to a cell-autonomous functional decline in skeletal muscle stem cells (MuSCs). Two-thirds of MuSCs from aged mice are intrinsically defective relative to MuSCs from young mice, with reduced capacity to repair myofibers and repopulate the stem cell reservoir in vivo following transplantation. This deficiency is correlated with a higher incidence of cells that express senescence markers and is due to elevated activity of the p38α and p38β mitogen-activated kinase pathway. We show that these limitations cannot be overcome by transplantation into the microenvironment of young recipient muscles. In contrast, subjecting the MuSC population from aged mice to transient inhibition of p38α and p38β in conjunction with culture on soft hydrogel substrates rapidly expands the residual functional MuSC population from aged mice, rejuvenating its potential for regeneration and serial transplantation as well as strengthening of damaged muscles of aged mice. These findings reveal a synergy between biophysical and biochemical cues that provides a paradigm for a localized autologous muscle stem cell therapy for the elderly.

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Figure 1: MuSCs from aged mice have diminished regenerative and self-renewal capacity, revealing an inherent stem cell defect.
Figure 2: MuSCs from aged mice are characterized by a senescence phenotype and elevated p38α/β MAPK signaling.
Figure 3: p38α/β MAPK inhibition induces proliferation and augments stem cell gene expression in MuSCs from aged mice grown in soft hydrogel cultures.
Figure 4: p38α/β inhibition and soft hydrogel substrate synergize to increase the total yield of functional aged stem cells.
Figure 5: Ex vivo–expanded progeny of MuSCs from aged mice reconstitute the stem cell reserve in vivo and can be serially transplanted.
Figure 6: Muscle strength restored in injured aged mice by transplantation of ex vivo–expanded progeny of MuSCs from aged mice.

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Acknowledgements

We thank K. Koleckar, P. Kraft, N. Nguyen, A. Thayer, C. Marceau, K. Magnusson and A. Ho for technical assistance; K. Havenstrite and R. Haynes for polymer synthesis; and the Stanford Center for Innovation in In-Vivo Imaging (SCI3), the Stanford Shared FACS Facility (SSFF) and IBM Almaden for technical support. This work was funded by US National Institutes of Health (NIH) training grant R25CA118681 and grant K99AG042491 (B.D.C.); NIH training grant T32CA009151 and grant K99AR061465 and California Institute for Regenerative Medicine training grant TG2-01159 (P.M.G.); and NIH grants U01HL100397, U01HL099997, R01AG020961, R01HL096113 and R01AG009521, an IBM Faculty Award, California Institute for Regenerative Medicine grants RT1-01001 and TR3-05501 and the Baxter Foundation (H.M.B.).

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B.D.C., P.M.G. and E.P. designed and performed experiments, analyzed data and wrote the manuscript. F.M., S.P.L., S.Y.C. and M.E.L. developed methods, performed experiments and analyzed data. S.L.D. developed methods and wrote the manuscript. H.M.B. designed experiments, analyzed data and wrote the manuscript.

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Correspondence to Penney M Gilbert or Helen M Blau.

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Cosgrove, B., Gilbert, P., Porpiglia, E. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat Med 20, 255–264 (2014). https://doi.org/10.1038/nm.3464

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