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A Role for p65 Signaling in Muscle‐derived Stem Cell Survival and Differentiation
Author(s) -
Proto Jonathan,
Lu Aiping,
Robbins Paul,
Huard Johnny
Publication year - 2010
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.24.1_supplement.lb406
Subject(s) - myogenesis , signal transduction , microbiology and biotechnology , oxidative stress , myocyte , stem cell , cell , cancer research , nf κb , skeletal muscle , cellular differentiation , myosin , mesenchymal stem cell , regeneration (biology) , biology , chemistry , biochemistry , endocrinology , gene
Cell therapies to repair damaged muscles with muscle‐derived stem cells (MDSCs) have proven to be superior to similar therapies with myoblasts. MDSCs can differentiate into various mesenchymal lineages and are highly resistant to oxidative stress, which previous work has shown may correlate with enhanced regenerative potential in vivo. Nuclear factor kappa B (NF‐kB), often considered an anti‐apoptotic signal, has recently been implicated in the muscle differentiation program. Two NF‐kB subunits, p65 and p50, are thought to play a negative role in early myogenesis. We investigated if inhibition of NF‐kB signaling in MDSCs would improve myogenic differentiation. We isolated MDSCs from 5 mo old WT and p65 heterozygous (p65+/−) mice and inhibited p65 signaling in WT MDSCs through the use of IKK‐2 Inhibitor IV (IKKi, Calbiochem), which selectively prevents IKK‐2 from activating the NF‐kB pathway. We also compared the survival under oxidative stress of p65+/− MDSCs to WT MDSCs using a live cell imaging system. We observed that treatment with IKKi enhanced MDSC differentiation into myosin heavy chain expressing myotubes. Interestingly, genetic reduction of p65 not only positively impacted cell survival under oxidative stress but also differentiation under stressful conditions. This data supports the conclusion that NF‐κB signaling has a regulatory role in MDSC survival and fate determination. Furthermore, NF‐kB signal transduction could represent a potential therapeutic target to improve muscle cell based therapies to enhance muscle regeneration in muscle disease and injury. 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.