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NF-κB negatively impacts the myogenic potential of muscle-derived stem cells

Niedernhofer, LJ and Wang, B and Guttridge, DC and Robbins, PD and Huard, J (2012) NF-κB negatively impacts the myogenic potential of muscle-derived stem cells. Molecular Therapy, 20 (3). 661 - 668. ISSN 1525-0016

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Abstract

Inhibition of the inhibitor of kappa B kinase (IKK)/nuclear factor-kappa B (NF-κB) pathway enhances muscle regeneration in injured and diseased skeletal muscle, but it is unclear exactly how this pathway contributes to the regeneration process. In this study, we examined the role of NF-κB in regulating the proliferation and differentiation of muscle-derived stem cells (MDSCs). MDSCs isolated from the skeletal muscles of p65/-mice (haploinsufficient for the p65 subunit of NF-κB) had enhanced proliferation and myogenic differentiation compared to MDSCs isolated from wild-type (wt) littermates. In addition, selective pharmacological inhibition of IKKΒ, an upstream activator of NF-κB, enhanced wt MDSC differentiation into myotubes in vitro. The p65/-MDSCs also displayed a higher muscle regeneration index than wt MDSCs following implantation into adult mice with muscular dystrophy. Additionally, using a muscle injury model, we observed that p65/-MDSC engraftments were associated with reduced inflammation and necrosis. These results suggest that inhibition of the IKK/NF-κB pathway represents an effective approach to improve the myogenic regenerative potential of MDSCs and possibly other adult stem cell populations. Moreover, our results suggest that the improved muscle regeneration observed following inhibition of IKK/NF-κB, is mediated, at least in part, through enhanced stem cell proliferation and myogenic potential. © The American Society of Gene & Cell Therapy.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Niedernhofer, LJniedernh@pitt.eduNIEDERNH
Wang, Bbingwang@pitt.eduBINGWANG
Guttridge, DC
Robbins, PDprobb@pitt.eduPROBB
Huard, J
Centers: Other Centers, Institutes, or Units > Stem Cell Research Center
Date: 1 January 2012
Date Type: Publication
Journal or Publication Title: Molecular Therapy
Volume: 20
Number: 3
Page Range: 661 - 668
DOI or Unique Handle: 10.1038/mt.2011.261
Schools and Programs: School of Medicine > Microbiology and Molecular Genetics
School of Medicine > Orthopaedic Surgery
Refereed: Yes
ISSN: 1525-0016
MeSH Headings: Animals; Cell Differentiation--drug effects; Cell Proliferation; Gene Expression Profiling; Heterozygote; I-kappa B Kinase--antagonists & inhibitors; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Mice, Knockout; Mice, SCID; Muscle Development--genetics; Muscle, Skeletal--cytology; Muscle, Skeletal--metabolism; Myoblasts--cytology; Myoblasts--metabolism; Myositis--genetics; Necrosis--genetics; Phenotype; Protein Kinase Inhibitors--pharmacology; Stem Cells--cytology; Stem Cells--metabolism; Transcription Factor RelA--genetics; Transcription Factor RelA--metabolism
Other ID: NLM PMC3293604
PubMed Central ID: PMC3293604
PubMed ID: 22158056
Date Deposited: 04 Apr 2014 15:42
Last Modified: 05 Jan 2019 16:00
URI: http://d-scholarship.pitt.edu/id/eprint/20843

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