title: Systemic Mesenchymal Stromal Cell Transplantation Prevents Functional Bone Loss in a Mouse Model of Age-Related Osteoporosis.
abstract: Age-related osteoporosis is driven by defects in the tissue-resident mesenchymal stromal cells (MSCs), a heterogeneous population of musculoskeletal progenitors that includes skeletal stem cells. MSC decline leads to reduced bone formation, causing loss of bone volume and the breakdown of bony microarchitecture crucial to trabecular strength. Furthermore, the low-turnover state precipitated by MSC loss leads to low-quality bone that is unable to perform remodeling-mediated maintenance--replacing old damaged bone with new healthy tissue. Using minimally expanded exogenous MSCs injected systemically into a mouse model of human age-related osteoporosis, we show long-term engraftment and markedly increased bone formation. This led to improved bone quality and turnover and, importantly, sustained microarchitectural competence. These data establish proof of concept that MSC transplantation may be used to prevent or treat human age-related osteoporosis.
  
  
  CONCLUSIONS
  This study shows that a single dose of minimally expanded mesenchymal stromal cells (MSCs) injected systemically into a mouse model of human age-related osteoporosis display long-term engraftment and prevent the decline in bone formation, bone quality, and microarchitectural competence. This work adds to a growing body of evidence suggesting that the decline of MSCs associated with age-related osteoporosis is a major transformative event in the progression of the disease. Furthermore, it establishes proof of concept that MSC transplantation may be a viable therapeutic strategy to treat or prevent human age-related osteoporosis.
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kiernan
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sally
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Grynpas
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada wstanford@ohri.ca jed.davies@utoronto.ca.
authors.forename: John E
authors.initials: JE
authors.lastname: Davies
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada Department of Cellular and Molecular Medicine and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada wstanford@ohri.ca jed.davies@utoronto.ca.
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
mesh_terms: D000818:Animals; D000067696:Ataxin-1 / Q000172:deficiency / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002469:Cell Separation / Q000379:methods; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006085:Graft Survival; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D018345:Mice, Knockout; D010012:Osteogenesis; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D010641:Phenotype; D013997:Time Factors
chemical_list: D000067696:Ataxin-1; C000593750:Atxn1 protein, mouse; D015415:Biomarkers
keywords: Mesenchymal stem cell; Osteoporosis; Sca-1; Stem cell transplantation; Tissue-specific stem cells