Modulation of fracture healing by the transient accumulation of senescent cells
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...
Guardado en:
| Autores principales: | , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
eLife Sciences Publications Ltd
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/8ba3a1c1e49d4f94bed1c548b3fd0494 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:8ba3a1c1e49d4f94bed1c548b3fd0494 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:8ba3a1c1e49d4f94bed1c548b3fd04942021-11-30T10:06:08ZModulation of fracture healing by the transient accumulation of senescent cells10.7554/eLife.699582050-084Xe69958https://doaj.org/article/8ba3a1c1e49d4f94bed1c548b3fd04942021-10-01T00:00:00Zhttps://elifesciences.org/articles/69958https://doaj.org/toc/2050-084XSenescent 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.Dominik SaulDavid G MonroeJennifer L RowseyRobyn Laura KosinskyStephanie J VosMadison L DoolittleJoshua N FarrSundeep KhoslaeLife Sciences Publications LtdarticlebonefracturecallusMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
bone fracture callus Medicine R Science Q Biology (General) QH301-705.5 |
| spellingShingle |
bone fracture callus Medicine R Science Q Biology (General) QH301-705.5 Dominik Saul David G Monroe Jennifer L Rowsey Robyn Laura Kosinsky Stephanie J Vos Madison L Doolittle Joshua N Farr Sundeep Khosla Modulation of fracture healing by the transient accumulation of senescent cells |
| description |
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. |
| format |
article |
| author |
Dominik Saul David G Monroe Jennifer L Rowsey Robyn Laura Kosinsky Stephanie J Vos Madison L Doolittle Joshua N Farr Sundeep Khosla |
| author_facet |
Dominik Saul David G Monroe Jennifer L Rowsey Robyn Laura Kosinsky Stephanie J Vos Madison L Doolittle Joshua N Farr Sundeep Khosla |
| author_sort |
Dominik Saul |
| title |
Modulation of fracture healing by the transient accumulation of senescent cells |
| title_short |
Modulation of fracture healing by the transient accumulation of senescent cells |
| title_full |
Modulation of fracture healing by the transient accumulation of senescent cells |
| title_fullStr |
Modulation of fracture healing by the transient accumulation of senescent cells |
| title_full_unstemmed |
Modulation of fracture healing by the transient accumulation of senescent cells |
| title_sort |
modulation of fracture healing by the transient accumulation of senescent cells |
| publisher |
eLife Sciences Publications Ltd |
| publishDate |
2021 |
| url |
https://doaj.org/article/8ba3a1c1e49d4f94bed1c548b3fd0494 |
| work_keys_str_mv |
AT dominiksaul modulationoffracturehealingbythetransientaccumulationofsenescentcells AT davidgmonroe modulationoffracturehealingbythetransientaccumulationofsenescentcells AT jenniferlrowsey modulationoffracturehealingbythetransientaccumulationofsenescentcells AT robynlaurakosinsky modulationoffracturehealingbythetransientaccumulationofsenescentcells AT stephaniejvos modulationoffracturehealingbythetransientaccumulationofsenescentcells AT madisonldoolittle modulationoffracturehealingbythetransientaccumulationofsenescentcells AT joshuanfarr modulationoffracturehealingbythetransientaccumulationofsenescentcells AT sundeepkhosla modulationoffracturehealingbythetransientaccumulationofsenescentcells |
| _version_ |
1718406695978270720 |