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

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      Abstract

      The aged suffer from progressive muscle weakness and regenerative failure. We demonstrate that muscle regeneration is impaired with aging due in part to a cell-autonomous functional decline in skeletal muscle stem cells (MuSCs). Two-thirds of aged MuSCs are intrinsically defective relative to young MuSCs, with reduced capacity to repair myofibers and repopulate the stem cell reservoir in vivo following transplantation due to a higher incidence of cells that express senescence markers and that have elevated p38α/β MAPK activity. We show that these limitations cannot be overcome by transplantation into the microenvironment of young recipient muscles. In contrast, subjecting the aged MuSC population to transient inhibition of p38α/β in conjunction with culture on soft hydrogel substrates rapidly expands the residual functional aged MuSC population, rejuvenating its potential for regeneration, serial transplantation, and strengthening 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 in aged individuals.

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      Most cited references 66

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      Matrix elasticity directs stem cell lineage specification.

      Microenvironments appear important in stem cell lineage specification but can be difficult to adequately characterize or control with soft tissues. Naive mesenchymal stem cells (MSCs) are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. Soft matrices that mimic brain are neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. During the initial week in culture, reprogramming of these lineages is possible with addition of soluble induction factors, but after several weeks in culture, the cells commit to the lineage specified by matrix elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types. Inhibition of nonmuscle myosin II blocks all elasticity-directed lineage specification-without strongly perturbing many other aspects of cell function and shape. The results have significant implications for understanding physical effects of the in vivo microenvironment and also for therapeutic uses of stem cells.
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        The selectivity of protein kinase inhibitors: a further update.

        The specificities of 65 compounds reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70-80 protein kinases. On the basis of this information, the effects of compounds that we have studied in cells and other data in the literature, we recommend the use of the following small-molecule inhibitors: SB 203580/SB202190 and BIRB 0796 to be used in parallel to assess the physiological roles of p38 MAPK (mitogen-activated protein kinase) isoforms, PI-103 and wortmannin to be used in parallel to inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 to be used in parallel with Src-I1 (Src inhibitor-1) to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 (MAPK kinase-1) or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB (protein kinase B/Akt), rapamycin to inhibit TORC1 [mTOR (mammalian target of rapamycin)-raptor (regulatory associated protein of mTOR) complex], CT 99021 to inhibit GSK3 (glycogen synthase kinase 3), BI-D1870 and SL0101 or FMK (fluoromethylketone) to be used in parallel to inhibit RSK (ribosomal S6 kinase), D4476 to inhibit CK1 (casein kinase 1), VX680 to inhibit Aurora kinases, and roscovitine as a pan-CDK (cyclin-dependent kinase) inhibitor. We have also identified harmine as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro. The results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes. Despite being used widely, many of the compounds that we analysed were too non-specific for useful conclusions to be made, other than to exclude the involvement of particular protein kinases in cellular processes.
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          SATELLITE CELL OF SKELETAL MUSCLE FIBERS

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            Author and article information

            Affiliations
            [1 ]Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
            [2 ]Institute of Biomaterials and Biomedical Engineering and Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
            [3 ]Department of Bioengineering, Stanford University School of Medicine, CA, USA
            [4 ]Department of Mechanical Engineering, Stanford University School of Medicine, CA, USA
            Author notes
            [* ] Corresponding authors: Helen M. Blau, Ph.D., Baxter Laboratory for Stem Cell Biology, Stanford University School of Medicine, 269 Campus Drive, CCSR 4215, Stanford, CA 94305, USA, Tel: 650-723-6209 / hblau@ 123456stanford.edu , Penney M. Gilbert, Ph.D., Institute of Biomaterials and Biomedical Engineering, University of Toronto, 160 College Street, Room 510, Toronto, Ontario M5S 3E1, Canada, Tel: 416-978-2501 / penney.gilbert@ 123456utoronto.ca
            Journal
            9502015
            8791
            Nat Med
            Nat. Med.
            Nature medicine
            1078-8956
            1546-170X
            18 February 2014
            16 February 2014
            March 2014
            01 September 2014
            : 20
            : 3
            : 255-264
            24531378
            3949152
            10.1038/nm.3464
            NIHMS555461

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            Medicine

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