Osteochondroprogenitor cells and neutrophils expressing p21 and senescence markers modulate fracture repair.
J Clin Invest
; 134(12)2024 May 16.
Article
em En
| MEDLINE
| ID: mdl-38753433
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+ cells expressing senescence markers, mainly as osteochondroprogenitors (OCHs) and neutrophils. Targeted genetic clearance of p21+ cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, p21+ cell clearance did not alter bone loss due to aging; conversely, p16+ cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Following fracture, p21+ neutrophils were enriched in signaling pathways known to induce paracrine stromal senescence, while p21+ 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+ 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+ versus p16+ senescent/senescent-like cells that may be leveraged for therapeutic opportunities.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Senescência Celular
/
Consolidação da Fratura
/
Inibidor de Quinase Dependente de Ciclina p21
/
Neutrófilos
Limite:
Animals
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article