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Mapping the Cellular Landscape of Calvarial Bone Repair Accelerated by Sympathetic Nerve Inhibition

ABSTRACT: Understanding the dynamic changes of cells during calvarial bone repair is crucial for identifying novel therapeutic targets to enhance bone regeneration. However, the cellular changes and intercellular communication during calvarial defect repair remain poorly understood. To address this, we performed single-cell RNA sequencing on tissues collected at different time points post-defect. Our analysis revealed a significant enhancement in intercellular communication following defect, particularly among stem cells, endothelial cells, pericytes, and macrophages. Pathways related to neurogenesis were significantly enriched after defect. Furthermore, we found that inhibiting sympathetic nerves promoted calvarial bone repair. Mechanistically, sympathetic nerve inhibition enhanced angiogenesis and osteogenesis by promoting interactions between pericytes and endothelial cells, generating a novel senescenced Arg1+ macrophages, which contributed to bone repair by secreting osteogenesis-related cytokines. Besides, inhibition of sympathetic nerves promotes the generation of Shisa3+ suture cell subpopulation and enhances osteogenic differentiation capacity. Importantly, senolytics abrogated the repair benefits brought about by sympathetic nerve inhibition, underscoring the critical role of senescent macrophages in the repair process.

ORGANISM(S): Mus musculus

PROVIDER: GSE298251 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:The methodology for the repair of critical-sized or non-union bone lesions has unpredictable efficacy due in part to our incomplete knowledge of bone repair and the biocompatibility of bone substitutes. Although human mesenchymal stem cells (hMSCs) differentiate into osteoblasts, which promote bone growth, their ability to repair bone has been unpredictable. We hypothesized that given the multi-stage process of osteogenesis, hMSC-mediated repair might be maximal at a specific time-point of healing. Utilizing a mouse model of calvarial healing, we demonstrate that the osteo-repair capacity of hMSCs can be substantially augmented by treatment with an inhibitor of peroxisome-proliferator-activated-receptor-γ, but efficacy is confined to the rapid osteogenic phase. Upon entry into the bone-remodeling phase, hMSC retention signals are lost, resulting in truncation of healing. To solve this limitation, we prepared a scaffold consisting of hMSC-derived extracellular matrix (ECM) containing the necessary biomolecules for extended site-specific hMSC retention. When inhibitor-treated hMSCs were co-administered with ECM, they remained at the injury well into the remodeling phase of healing, which resulted in reproducible and complete repair of critical-sized defects in 3 weeks. These data suggest that hMSC-derived ECM and inhibitor-treated hMSCs could be employed at optimal times to substantially and reproducibly improve bone repair. To gain insight into the superior healing potential of GW-hMSCs and also what might be accounting for their extended engraftment, microarray analyses on the RNA extracted from the calvarial tissue recovered after days 5 and 14 were performed. Equal amounts of total RNA from 4 animals per group and time point were pooled and animals receiving control (DMSO) or peroxisome proliferator-activated receptor-gamma inhibitor GW9662-treated hMSCs were compared with the assumption that murine cross-hybridization would be constant throughout the samples and thus be subtracted from the analysis.

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Mapping the Cellular Landscape of Calvarial Bone Repair Accelerated by Sympathetic Nerve Inhibition

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