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Modulation of fracture healing by the transient accumulation of senescent cells.

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 (Cdkn2a^LUC) containing a Cdkn2a^Ink4a-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.

SUBMITTER: Saul D

PROVIDER: S-EPMC8526061 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Delayed fracture healing and fracture non-unions impose an enormous burden on individuals and society. Successful healing requires tight communication between immune cells and bone cells. Macrophages can be found in all healing phases. Due to their high plasticity and long life span, they represent good target cells for modulation. In the past, extremely low frequency pulsed electromagnet fields (ELF-PEMFs) have been shown to exert cell-specific effects depending on the field conditions. Thus, the aim was to identify the specific ELF-PEMFs able to modulate macrophage activity to indirectly promote mesenchymal stem/stromal cell (SCP-1 cells) function. After a blinded screening of 22 different ELF-PEMF, two fields (termed A and B) were further characterized as they diversely affected macrophage function. These two fields have similar fundamental frequencies (51.8 Hz and 52.3 Hz) but are emitted in different groups of pulses or rather send-pause intervals. Macrophages exposed to field A showed a pro-inflammatory function, represented by increased levels of phospho-Stat1 and CD86, the accumulation of ROS, and increased secretion of pro-inflammatory cytokines. In contrast, macrophages exposed to field B showed anti-inflammatory and pro-healing functions, represented by increased levels of Arginase I, increased secretion of anti-inflammatory cytokines, and growth factors are known to induce healing processes. The conditioned medium from macrophages exposed to both ELF-PEMFs favored the migration of SCP-1 cells, but the effect was stronger for field B. Furthermore, the conditioned medium from macrophages exposed to field B, but not to field A, stimulated the expression of extracellular matrix genes in SCP-1 cells, i.e., COL1A1, FN1, and BGN. In summary, our data show that specific ELF-PEMFs may affect immune cell function. Thus, knowing the specific ELF-PEMFs conditions and the underlying mechanisms bears great potential as an adjuvant treatment to modulate immune responses during pathologies, e.g., fracture healing.

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Modulation of fracture healing by the transient accumulation of senescent cells.

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