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Inhibition of NF‐kB enhances the characteristics of aged muscle stem cells
Author(s) -
Proto Jonathan D.,
Lu Aiping,
Huard Johnny
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.615.6
Evidence indicates that the regenerative capacity of adult stem and progenitor cells declines during aging. Recent reports of age‐associated changes in skeletal muscle have found that progenitor cell aging may be reversible. These studies suggest that aged tissues may harbor stem cell populations with a dormant capacity for regeneration, highlighting the importance of identifying the molecular signals responsible for suppressing stem cell function. The NF‐kB subunit p65 has been found to negatively regulate myoblast differentiation. We previously found that MDSCs isolated from mice heterozygous for p65 have enhanced cell proliferation, survival under oxidative stress, differentiation in vitro , and muscle regeneration capacity in vivo . We hypothesize that classical activation of the IKK/NF‐kB pathway suppresses the myogenic regeneration capacity of muscle‐derived stem cells (MDSCs), and that selective blockade of NF‐kB is a viable molecular strategy for enhancing the function of stem cells derived from aged tissue. We have isolated MDSCs from young (14 day old) and aged (24 month old) wild type mice using the modified preplate technique. In vitro differentiation assays have confirmed that MDSC myogenic potential declines over time. However, treatment with a small molecule NF‐kB inhibitor restores myogenesis in aged MDSCs to levels equal to those of young cells, a result that we propose to further investigate in vivo using an mdx transplant model of muscle regeneration. Additionally, NF‐kB inhibition also increases aged MDSC resistance to oxidative stress and increases proliferation in vitro . Therefore, targeting the NF‐kB pathway may represent one strategy for enhancing the efficacy of autologous cell therapies in aging patients. This work was supported in part by the Henry J. Mankin Endowed Chair for Orthopaedic Research at the University of Pittsburgh, the William F. and Jean W. Donaldson Chair at Children's Hospital of Pittsburgh, and the Hirtzel Foundation.