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Modulation of fracture healing by the transient accumulation of senescent cells

Citation

Saul, Dominik et al. (2022), Modulation of fracture healing by the transient accumulation of senescent cells, Dryad, Dataset, https://doi.org/10.5061/dryad.prr4xgxm6

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.

Funding

Deutsche Forschungsgemeinschaft, Award: 413501650

National Institutes of Health, Award: AG062413

National Institutes of Health, Award: AG065868

National Institutes of Health, Award: AR070241

National Institutes of Health, Award: AG063707

Dr. Mildred Scheel Stiftung für Krebsforschung

National Institute on Aging, Award: P01 AG062413

National Institute on Aging, Award: R21 AG065868

National Institute on Aging, Award: R01 AG063707

National Institute of Diabetes and Digestive and Kidney Diseases, Award: R01 DK128552

German Research Foundation, Award: 413501650