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Osteochondroprogenitor cells and neutrophils expressing p21 and senescence markers modulate fracture repair
Dominik Saul, … , David G. Monroe, Sundeep Khosla
Dominik Saul, … , David G. Monroe, Sundeep Khosla
Published May 16, 2024
Citation Information: J Clin Invest. 2024;134(12):e179834. https://doi.org/10.1172/JCI179834.
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Research Article Aging Bone biology Article has an altmetric score of 5

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

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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.

Authors

Dominik Saul, Madison L. Doolittle, Jennifer L. Rowsey, Mitchell N. Froemming, Robyn L. Kosinsky, Stephanie J. Vos, Ming Ruan, Nathan K. LeBrasseur, Abhishek Chandra, Robert J. Pignolo, João F. Passos, Joshua N. Farr, David G. Monroe, Sundeep Khosla

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Figure 4

p21+ callus cells are largely highly secretory OCH cells and mature neutrophils.

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p21+ callus cells are largely highly secretory OCH cells and mature neut...
(A) Schematic of p21+ cell isolation and scRNA-seq using the p21 reporter mice. (B) GFP+ cells were significantly higher in the fractured compared with the unfractured contralateral side and an unfractured mouse tibia. n = 10 fractured (n = 4 female, n = 6 male), n = 8 contralateral sides (n = 4 female, n = 4 male), n = 6 unfractured (n = 3 female, n = 3 male). (C) p21Cip1, Cxcl2, Vegfa, and Tnfa mRNA expression was significantly enriched in GFP+ cells. n = 8 mice (n = 4 male, n = 4 female). (D) scRNA-seq analysis was performed on 5,994 total callus cells from n = 4 mice (n = 2 male, n = 2 female). (E) Differentially upregulated mRNA transcripts in p21+ cells. (F) Proportion of p21+ cells and (G) SenMayo gene enrichment analysis among clustered cell populations. (H and I) Predicted secretory strength relationships in callus cells among all signaling pathways and (J) TGF-β signaling by CellChat. *P < 0.05; **P < 0.01; ***P < 0.001 by 1-way ANOVA with Tukey’s correction (B) or Mann-Whitney U test (C, GFP+ vs. GFP–).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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