Inhibition of NF-κB improves the stress resistance and myogenic differentiation of MDSPCs isolated from naturally aged mice

A decline in the regenerative capacity of adult stem cells with aging is well documented. As a result of this decline, the efficacy of autologous stem cell therapies is likely to decline with increasing donor age. In these cases, strategies to restore the function of aged stem cells would have clinical utility. Globally, the transcription factor NF-κB is up-regulated in aged tissues. Given the negative role that NF-κB plays in myogenesis, we investigated whether the age-related decline in the function of muscle-derived stem/progenitor cells (MDSPCs) could be improved by inhibition of NF-κB. Herein, we demonstrate that pharmacologic or genetic inhibition of NF-κB activation increases myogenic differentiation and improves resistance to oxidative stress. Our results suggest that MDSPC “aging” may be reversible, and that pharmacologic targeting of pathways such as NF-κB may enhance the efficacy of cell-based therapies.

[1]  A. Wagers,et al.  Age-associated NF-κB signaling in myofibers alters the satellite cell niche and re-strains muscle stem cell function , 2016, Aging.

[2]  Freddie H. Fu,et al.  mTOR signaling plays a critical role in the defects observed in muscle‐derived stem/progenitor cells isolated from a murine model of accelerated aging , 2016, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[3]  S. Kang,et al.  Health Span‐Extending Activity of Human Amniotic Membrane‐ and Adipose Tissue‐Derived Stem Cells in F344 Rats , 2015, Stem cells translational medicine.

[4]  G. Daley,et al.  NF-κB activation impairs somatic cell reprogramming in ageing , 2015, Nature Cell Biology.

[5]  K. Rudolph,et al.  Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer , 2015, Cell stem cell.

[6]  M. Szychlinska,et al.  Mesenchymal stem cells-based therapy as a potential treatment in neurodegenerative disorders: is the escape from senescence an answer? , 2015, Neural regeneration research.

[7]  P. Robbins,et al.  NF-κB inhibition reveals a novel role for HGF during skeletal muscle repair , 2015, Cell Death and Disease.

[8]  H. Warner.  NIA’s intervention testing program at 10 years of age , 2015, AGE.

[9]  Daohong Zhou,et al.  Rapamycin Enhances Long-Term Hematopoietic Reconstitution of Ex Vivo Expanded Mouse Hematopoietic Stem Cells by Inhibiting Senescence , 2014, Transplantation.

[10]  J. Huard,et al.  Muscle-derived stem/progenitor cell dysfunction in Zmpste24-deficient progeroid mice limits muscle regeneration , 2013, Stem Cell Research & Therapy.

[11]  Simon C Watkins,et al.  NF-κB inhibition delays DNA damage-induced senescence and aging in mice. , 2012, The Journal of clinical investigation.

[12]  B. Wang,et al.  NF-κB negatively impacts the myogenic potential of muscle-derived stem cells. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[13]  P. Robbins,et al.  Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model , 2012, Nature Communications.

[14]  D. Charron,et al.  Age‐related changes in human hematopoietic stem/progenitor cells , 2011, Aging cell.

[15]  Xiao-bing Fu,et al.  MSCs: Biological characteristics, clinical applications and their outstanding concerns , 2011, Ageing Research Reviews.

[16]  Marco Pahor,et al.  Rapamycin fed late in life extends lifespan in genetically heterogeneous mice , 2009, Nature.

[17]  A. Salminen,et al.  NF-κB Signaling in the Aging Process , 2009, Journal of Clinical Immunology.

[18]  Kenneth L. Hensley,et al.  Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice , 2008, Aging cell.

[19]  B. Zheng,et al.  Isolation of a slowly adhering cell fraction containing stem cells from murine skeletal muscle by the preplate technique , 2008, Nature Protocols.

[20]  Zhijian Yang,et al.  Low‐dose aspirin promotes endothelial progenitor cell migration and adhesion and prevents senescence , 2008, Cell biology international.

[21]  S. Dimmeler,et al.  Aging and disease as modifiers of efficacy of cell therapy. , 2008, Circulation research.

[22]  Eran Segal,et al.  Motif module map reveals enforcement of aging by continual NF-κB activity , 2007 .

[23]  C. Keller,et al.  Increased Wnt Signaling During Aging Alters Muscle Stem Cell Fate and Increases Fibrosis , 2007, Science.

[24]  I. Conboy,et al.  Loss of stem cell regenerative capacity within aged niches , 2007, Aging cell.

[25]  Huating Wang,et al.  NF-κB Regulation of YY1 Inhibits Skeletal Myogenesis through Transcriptional Silencing of Myofibrillar Genes , 2007, Molecular and Cellular Biology.

[26]  R. Westendorp,et al.  β‐Galactosidase Activity as a Biomarker of Replicative Senescence during the Course of Human Fibroblast Cultures , 2007, Annals of the New York Academy of Sciences.

[27]  E. Schleicher,et al.  Immunomorphological Analysis of RAGE Receptor Expression and NF‐κB Activation in Tissue Samples from Normal and Degenerated Intervertebral Discs of Various Ages , 2007, Annals of the New York Academy of Sciences.

[28]  S. Radhakrishnan,et al.  Pro-apoptotic role of NF-κB: Implications for cancer therapy , 2006 .

[29]  Freddie H Fu,et al.  Cartilage repair using bone morphogenetic protein 4 and muscle-derived stem cells. , 2006, Arthritis and rheumatism.

[30]  Johnny Huard,et al.  Differential myocardial infarct repair with muscle stem cells compared to myoblasts. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[31]  Michael Karin,et al.  IKK/NF-κB signaling: balancing life and death – a new approach to cancer therapy , 2005 .

[32]  G. van Zant,et al.  Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. , 2005, Blood.

[33]  I. Weissman,et al.  Rejuvenation of aged progenitor cells by exposure to a young systemic environment , 2005, Nature.

[34]  Thomas A Rando,et al.  Aging, Stem Cells and Tissue Regeneration: Lessons from Muscle , 2005, Cell cycle.

[35]  C. Abbadie,et al.  Involvement of Rel/NF-κB transcription factors in senescence , 2003, Experimental Gerontology.

[36]  J. Greenberger,et al.  Modeling Stem Cell Population Growth: Incorporating Terms for Proliferative Heterogeneity , 2003, Stem cells.

[37]  Johnny Huard,et al.  BMP4-expressing muscle-derived stem cells differentiate into osteogenic lineage and improve bone healing in immunocompetent mice. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[38]  Michael Karin,et al.  NF-κB at the crossroads of life and death , 2002, Nature Immunology.

[39]  T. Hofmann,et al.  The pro- or anti-apoptotic function of NF-kappaB is determined by the nature of the apoptotic stimulus. , 2000, European journal of biochemistry.

[40]  C. Trautwein,et al.  NFκB Mediates Apoptosis through Transcriptional Activation of Fas (CD95) in Adenoviral Hepatitis* , 2000, The Journal of Biological Chemistry.

[41]  Chris Albanese,et al.  NF-κB Controls Cell Growth and Differentiation through Transcriptional Regulation of Cyclin D1 , 1999, Molecular and Cellular Biology.

[42]  C Roskelley,et al.  A biomarker that identifies senescent human cells in culture and in aging skin in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[43]  K. Tobita,et al.  Human skeletal muscle cells with a slow adhesion rate after isolation and an enhanced stress resistance improve function of ischemic hearts. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[44]  J. Vella,et al.  Antioxidant levels represent a major determinant in the regenerative capacity of muscle stem cells. , 2009, Molecular biology of the cell.

[45]  D. Guttridge,et al.  The RelA/p65 subunit of NF‐κB specifically regulates cyclin D1 protein stability: Implications for cell cycle withdrawal and skeletal myogenesis , 2009, Journal of cellular biochemistry.

[46]  Eran Segal,et al.  Motif module map reveals enforcement of aging by continual NF-kappaB activity. , 2007, Genes & development.

[47]  S. Radhakrishnan,et al.  Pro-apoptotic role of NF-kappaB: implications for cancer therapy. , 2006, Biochimica et biophysica acta.

[48]  C. Abbadie,et al.  Involvement of Rel/NF-kappa B transcription factors in senescence. , 2003, Experimental gerontology.

[49]  Michael Karin,et al.  NF-kappaB at the crossroads of life and death. , 2002, Nature immunology.