Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 14, Pages 6995-7004Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1810692116
Keywords
regeneration; skeletal stem cell; senescence; inflammation; bone healing
Categories
Funding
- NIH [S10 OD010751]
- NIH/National Cancer Institute [P30CA016087]
- NIH/National Institute on Aging [1R01AG056169]
- NIH/National Institute of Arthritis and Musculoskeletal and Skin [K08AR069099]
- Orthopaedic Research and Education Foundation
- Orthopaedic Trauma Association - Zimmer Biomet, Depuy Synthes
- Society of Military Orthopaedic Surgeons
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Aging is associated with impaired tissue regeneration. Stem cell number and function have been identified as potential culprits. We first demonstrate a direct correlation between stem cell number and time to bone fracture union in a human patient cohort. We then devised an animal model recapitulating this age-associated decline in bone healing and identified increased cellular senescence caused by a systemic and local proinflammatory environment as the major contributor to the decline in skeletal stem/progenitor cell (SSPC) number and function. Decoupling age-associated systemic inflammation from chronological aging by using transgenic Nfkb1KO mice, we determined that the elevated inflammatory environment, and not chronological age, was responsible for the decrease in SSPC number and function. By using a pharmacological approach inhibiting NF-kappa B activation, we demonstrate a functional rejuvenation of aged SSPCs with decreased senescence, increased SSPC number, and increased osteogenic function. Unbiased, whole-genome RNA sequencing confirmed the reversal of the aging phenotype. Finally, in an ectopic model of bone healing, we demonstrate a functional restoration of regenerative potential in aged SSPCs. These data identify aging-associated inflammation as the cause of SSPC dysfunction and provide mechanistic insights into its reversal.
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