Modulation of fracture healing by the transient accumulation of senescent cells
- Mayo Clinic, United States
Abstract
Senescent cells have detrimental effects across tissues with aging but may have beneficial effects on tissue repair, specifically on skin wound healing. However, the potential role of senescent cells in fracture healing has not been defined. Here, we performed an in silico analysis of public mRNAseq data and found that senescence and senescence-associated secretory phenotype (SASP) markers increased during fracture healing. We next directly established that the expression of senescence biomarkers increased markedly during murine fracture healing. We also identified cells in the fracture callus that displayed hallmarks of senescence, including distension of satellite heterochromatin and telomeric DNA damage; the specific identity of these cells, however, requires further characterization. Then, using a genetic mouse model (Cdkn2aLUC) containing a Cdkn2aInk4a-driven luciferase reporter, we demonstrated transient in vivo senescent cell accumulation during callus formation. Finally, we intermittently treated young adult mice following fracture with drugs that selectively eliminate senescent cells ('senolytics', Dasatinib plus Quercetin), and showed that this regimen both decreased senescence and SASP markers in the fracture callus and significantly accelerated the time course of fracture healing. Our findings thus demonstrate that senescent cells accumulate transiently in the murine fracture callus and, in contrast to the skin, their clearance does not impair but rather improves fracture healing.
Data availability
RNA-seq data was generated from GSE152677.
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Transcriptional profiling of intramembranous and endochondral ossification after fracture in miceNCBI Gene Expression Omnibus, GSE152677.
Article and author information
Author details
Funding
National Institute on Aging (P01 AG062413)
- Joshua N Farr
National Institute on Aging (R21 AG065868)
- Joshua N Farr
National Institute on Aging (R01 AG063707)
- David G Monroe
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK128552)
- Joshua N Farr
German Research Foundation (413501650)
- Dominik Saul
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal studies were performed under protocols approved by the Institutional Animal Care and Use Committee (IACUC), and experiments were performed in accordance with Mayo Clinic IACUC guidelines.
Copyright
© 2021, Saul et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Modulation of fracture healing by the transient accumulation of senescent cells
eLife 10:e69958.
https://doi.org/10.7554/eLife.69958
