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Osteochondroprogenitor cells and neutrophils expressing p21 and senescence markers modulate fracture repair

Authors :
Saul, Dominik
Doolittle, Madison L.
Rowsey, Jennifer L.
Froemming, Mitchell N.
Kosinsky, Robyn L.
Vos, Stephanie J.
Ruan, Ming
LeBrasseur, Nathan K.
Chandra, Abhishek
Pignolo, Robert J.
Passos, Joao F.
Farr, Joshua N.
Monroe, David G.
Khosla, Sundeep
Source :
Journal of Clinical Investigation. June 15, 2024, Vol. 134 Issue 12
Publication Year :
2024

Abstract

Cells expressing features of senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Here, we used skeletal injury as a model and identified the rapid appearance following fracture of [p21.sup.+] cells expressing senescence markers, mainly as osteochondroprogenitors (OCHs) and neutrophils. Targeted genetic clearance of [p21.sup.+] cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, [p21.sup.+] cell clearance did not alter bone loss due to aging; conversely, [p16.sup.+] cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Following fracture, [p21.sup.+] neutrophils were enriched in signaling pathways known to induce paracrine stromal senescence, while [p21.sup.+] OCHs were highly enriched in senescence-associated secretory phenotype factors known to impair bone formation. Further analysis revealed an injury-specific stem cell-like OCH subset that was [p21.sup.+] and highly inflammatory, with a similar inflammatory mesenchymal population (fibro-adipogenic progenitors) evident following muscle injury. Thus, intercommunicating senescent-like neutrophils and mesenchymal progenitor cells were key regulators of tissue repair in bone and potentially across tissues. Moreover, our findings established contextual roles of [p21.sup.+] versus [p16.sup.+] senescent/ senescent-like cells that may be leveraged for therapeutic opportunities.<br />Introduction At the cellular level, aging is characterized by several hallmarks, including cellular senescence (1), which is driven by an increase in the cyclin-dependent kinase inhibitors Cdknla (p21) and/or Cdknla [...]

Details

Language :
English
ISSN :
00219738
Volume :
134
Issue :
12
Database :
Gale General OneFile
Journal :
Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
edsgcl.801951061
Full Text :
https://doi.org/10.1172/JCI179834