Muscle stem cell therapy in a mouse model of premature aging

Summary

Principal Investigator: Johnny Huard
Abstract: DESCRIPTION (provided by applicant): It is well-known that aged individuals, an expanding demographic in the United States, have a dramatically increased risk of numerous debilitating diseases including bone fractures, cardiovascular disease, cognitive impairment, diabetes and cancer. Although the molecular basis of the progressive loss of homeostatic reserve with aging is controversial, there are several lines of evidence that implicate accumulated DNA damage as a major determinant in the progression of age-related pathology. In particular, the majority of human progerias (or syndromes of accelerated aging) are caused by inherited mutations in genes required for genome repair and maintenance, including XPF. ERCC1-XPF protein complex is a highly conserved endonuclease that is required for at least two DNA repair mechanisms: nucleotide excision repair (NER) and DNA interstrand crosslink repair. We have several progeroid mouse models of ERCC1-XPF deficiency including Ercc1-/- and Ercc1-/ , which express levels of ERCC1-XPF at 0% and 10% of normal, respectively. The average life span of the Ercc1-/- mice is 21 days and that of the Ercc1-/ mice is 7 months. Both mice develop age-related pathologies including ataxia, kyphosis, cachexia, disc degeneration, osteoporosis, incontinence, epidermal atrophy, sarcopenia, bone marrow degeneration and liver as well as kidney dysfunction. We previously isolated and characterized a population of muscle-derived stem cells (MDSCs) that displays a high regenerative capacity in various tissues of the musculoskeletal system. Our preliminary results suggest that MDSCs isolated from progeroid ERCC1-XPF deficient mice have proliferation and differentiation defects. Furthermore, injection of wild type (wt) MDSCs into Ercc1-/- mice results in their engraftment into multiple tissues and significantly extends lifespan. Thus we hypothesize that a defect in the adult stem cell compartment in ERCC1-XPF deficient mice is involved in their dramatically accelerated aging and that stem cell therapy may represent a potential strategy to prevent or delay age-associated debilitating changes. The focus of this proposal will be on documenting and characterizing the defect in MDSCs in our unique progeroid mouse models and on demonstrating the ability of transplantation of functional MDSCs to delay the onset of age-related pathologies. PUBLIC HEALTH RELEVANCE: Aging is characterized by the progressive erosion of all organ systems which places the elderly at an increased risk of numerous debilitating diseases and organ system failures including cardiovascular disease, dementia, bone fractures, sarcopenia, and cancer. Demographic studies indicate that the number of individuals aged greater than 65 will double in the next 25 years and impose an unprecedented burden on the U.S. health care system. This research proposal is highly significant in that it has the potential to not only reveal a biological mechanism(s) of aging (defect in stem cell compartment), but could also lead to the development of stem cell therapies which could delay or ameliorate the pathologies associated with aging;therefore, identifying strategies, such as stem cell transplantation, is essential for maintaining the health of our aging population.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Regulation of immune responses by extracellular vesicles
    Paul D Robbins
    Department of Metabolism and Aging, The Scripps Research Institute, 130 Scripps Way 3B3, Jupiter, Florida 33458, USA
    Nat Rev Immunol 14:195-208. 2014
  2. pmc Pharmacologic IKK/NF-κB inhibition causes antigen presenting cells to undergo TNFα dependent ROS-mediated programmed cell death
    Jeremy S Tilstra
    1 Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219 2
    Sci Rep 4:3631. 2014
  3. pmc An overview of underlying causes and animal models for the study of age-related degenerative disorders of the spine and synovial joints
    Nam Vo
    Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, E1641 Biomedical Science Tower, Pittsburgh, Pennsylvania 15261, USA
    J Orthop Res 31:831-7. 2013
  4. pmc DNA damage drives accelerated bone aging via an NF-κB-dependent mechanism
    Qian Chen
    Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    J Bone Miner Res 28:1214-28. 2013
  5. pmc NF-κB inhibition delays DNA damage-induced senescence and aging in mice
    Jeremy S Tilstra
    Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    J Clin Invest 122:2601-12. 2012
  6. pmc Plasma-derived MHC class II+ exosomes from tumor-bearing mice suppress tumor antigen-specific immune responses
    Chenjie Yang
    Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA
    Eur J Immunol 42:1778-84. 2012
  7. pmc Exosomes released from Mycoplasma infected tumor cells activate inhibitory B cells
    Chenjie Yang
    Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
    PLoS ONE 7:e36138. 2012
  8. pmc NF-κB in Aging and Disease
    Jeremy S Tilstra
    Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Aging Dis 2:449-65. 2011
  9. pmc Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model
    Mitra Lavasani
    Stem Cell Research Center, 206 Bridgeside Point II, 450 Technology Drive, Pittsburgh, Pennsylvania 15219, USA
    Nat Commun 3:608. 2012
  10. pmc The roles of tumor-derived exosomes in cancer pathogenesis
    Chenjie Yang
    Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA
    Clin Dev Immunol 2011:842849. 2011

Scientific Experts

  • James R Goss
  • Paul D Robbins
  • Laura J Niedernhofer
  • Jeremy S Tilstra
  • Chenjie Yang
  • Nam Vo
  • Andria R Robinson
  • Cheryl L Clauson
  • Aiping Lu
  • Johnny Huard
  • Mitra Lavasani
  • Qian Chen
  • Denis C Guttridge
  • Seon Hee Kim
  • SHAIVAL H DAVE
  • Jing Zhao
  • Scott E Plevy
  • Daniel F Gaddy
  • Christopher H Evans
  • James Kang
  • Hongjiao Ouyang
  • Harry C Blair
  • Kai Liu
  • Lloydine Jacobs
  • Luigi Aurelio Nasto
  • Bahar Ahani
  • George A Garinis
  • Paula R Clemens
  • Jin Wang
  • Claudette M St Croix
  • Yue Harn Ng
  • Lulin Guo
  • Siobhán Q Gregg
  • Jonathan D Proto
  • Donna B Stolz
  • Geetha Chalasani
  • MELANIE A RUFFNER
  • Simon C Watkins
  • Daniel P Reay
  • Luigi A Nasto
  • Joseph M Feduska
  • Chelsea H Feldman
  • Ying Tang
  • Bing Wang
  • MinJung Song
  • Yinsheng Wang
  • Arvydas Usas
  • Nicole R Bianco

Detail Information

Publications13

  1. ncbi Regulation of immune responses by extracellular vesicles
    Paul D Robbins
    Department of Metabolism and Aging, The Scripps Research Institute, 130 Scripps Way 3B3, Jupiter, Florida 33458, USA
    Nat Rev Immunol 14:195-208. 2014
    ..Given the tremendous therapeutic potential of extracellular vesicles, this Review focuses on their role in modulating immune responses, as well as their potential therapeutic applications. ..
  2. pmc Pharmacologic IKK/NF-κB inhibition causes antigen presenting cells to undergo TNFα dependent ROS-mediated programmed cell death
    Jeremy S Tilstra
    1 Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219 2
    Sci Rep 4:3631. 2014
    ..NF-κB-inhibition-induced PCD of APC may be a key mechanism through which therapeutic targeting of NF-κB reduces inflammatory pathologies. ..
  3. pmc An overview of underlying causes and animal models for the study of age-related degenerative disorders of the spine and synovial joints
    Nam Vo
    Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, E1641 Biomedical Science Tower, Pittsburgh, Pennsylvania 15261, USA
    J Orthop Res 31:831-7. 2013
    ....
  4. pmc DNA damage drives accelerated bone aging via an NF-κB-dependent mechanism
    Qian Chen
    Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    J Bone Miner Res 28:1214-28. 2013
    ..These results demonstrate that DNA damage drives osteoporosis through an NF-κB-dependent mechanism. Therefore, the NF-κB pathway represents a novel therapeutic target to treat aging-related bone disease...
  5. pmc NF-κB inhibition delays DNA damage-induced senescence and aging in mice
    Jeremy S Tilstra
    Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    J Clin Invest 122:2601-12. 2012
    ..IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging...
  6. pmc Plasma-derived MHC class II+ exosomes from tumor-bearing mice suppress tumor antigen-specific immune responses
    Chenjie Yang
    Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA
    Eur J Immunol 42:1778-84. 2012
    ..These results demonstrate that circulating host-derived, MHC class II(+) exosomes in tumor-bearing hosts are able to suppress the immune response specific to tumor antigens...
  7. pmc Exosomes released from Mycoplasma infected tumor cells activate inhibitory B cells
    Chenjie Yang
    Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
    PLoS ONE 7:e36138. 2012
    ..These results suggest that mycoplasmas infecting tumor cells can exploit the exosome pathway to disseminate their own components and modulate the activity of immune cells, in particular, activate B cells with inhibitory activity...
  8. pmc NF-κB in Aging and Disease
    Jeremy S Tilstra
    Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Aging Dis 2:449-65. 2011
    ..In addition, NF-κB activation is linked with many of the known lifespan regulators including insulin/IGF-1, FOXO, SIRT, mTOR, and DNA damage. Thus NF-κB represents a possible therapeutic target for extending mammalian healthspan...
  9. pmc Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model
    Mitra Lavasani
    Stem Cell Research Center, 206 Bridgeside Point II, 450 Technology Drive, Pittsburgh, Pennsylvania 15219, USA
    Nat Commun 3:608. 2012
    ..These results establish that adult stem/progenitor cell dysfunction contributes to ageing-related degeneration and suggests a therapeutic potential of post-natal stem cells to extend health...
  10. pmc The roles of tumor-derived exosomes in cancer pathogenesis
    Chenjie Yang
    Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA
    Clin Dev Immunol 2011:842849. 2011
    ..These different effects of tumor-derived exosomes contribute to the pathogenesis of cancer. This review will discuss the roles of tumor-derived exosomes in cancer pathogenesis, therapy, and diagnostics...
  11. pmc NF-κB negatively impacts the myogenic potential of muscle-derived stem cells
    Aiping Lu
    Stem Cell Research Center, School of Medicine and Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA
    Mol Ther 20:661-8. 2012
    ..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...
  12. pmc Tumor-derived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model
    Chenjie Yang
    Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
    PLoS ONE 6:e22517. 2011
    ..Taken together, our results suggest a role for tumor-derived exosomes in inducing tumor antigen-specific immunosuppression, possibly by modulating the function of APCs...
  13. pmc Premature aging-related peripheral neuropathy in a mouse model of progeria
    James R Goss
    Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA 15213 1863, USA
    Mech Ageing Dev 132:437-42. 2011
    ..This provides strong evidence that DNA damage can drive peripheral neuropathy and offers a rapid and novel model to test therapies...