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Mapping Somatosensory Afferent Circuitry to Bone Identifies Neurotrophic Signals Required for Fracture Healing

ABSTRACT: A central feature of bone injury is the sensation of pain, transmitted by nociceptive sensory nerves that innervate the skeleton. Indeed skeletal-innervating peripheral neurons are known to regulate skeletal repair and pathophysiology. Here, using retrograde peripheral nerve labeling and single cell RNA sequencing (scRNA-seq), we precisely identify the unique molecular signature of skeletal-innervating sensory neurons and the shifting neuronal transcriptomic landscape after bone fracture. Two methods to surgically or genetically denervate fractured bones were used in combination with scRNA-seq to implicate defective mesenchymal cell proliferation and osteodifferentiation as underlying the poor bone repair capacity in the presence of attenuated skeletal innervation. Multi-tissue scRNA-seq and interactome analyses implicated neuron-derived FGF9 as a potent regulator of fracture repair, a finding confirmed by in vitro assessments of neuron-to-skeletal mesenchyme interactions. Identification of FGF9 as a novel, neuron-derived skeletal growth factor uncovers a potential target for improving tissue repair.

ORGANISM(S): Mus musculus

PROVIDER: GSE265817 | GEO | 2025/10/22

REPOSITORIES: GEO

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Project description:The phases of fracture healing have been well characterized. However, the exact source and genetic profile of the skeletal progenitors that participate in bone repair is somewhat unclear. Sox9 expression in skeletal elements precedes bone and cartilage formation and a Sox9+ cell type is retained in the adult periosteum. We hypothesized that Sox9+ periosteal cells are multipotent skeletal progenitors normally participating in fracture repair. To test this hypothesis we used tamoxifen (TM)-mediated lineage tracing of Sox9+ cells in Sox9CreErt2:Td-Tomato mice. TM injection indelibly labels Sox9+ cells and all their descendants with the fluorescent reporter protein Td-Tomato. Intact mouse femora were harvested 2 weeks after TM injection and analyzed by histology and immunostaining and RNA sequencing, to evaluate the skeletal distribution and gene expression profile of Td-Tomato positive cells in the adult femur. To assess the role of these cells in fracture repair, mice underwent a closed mid-diaphyseal femoral fracture and their hind limbs were harvested at 3, 9 or 56 days post-fracture to assess the contribution of Sox9+ and Td-tomato+ cells in the fracture healing process. In the intact adult mouse femur, Td-Tomato-labelled cells were observed in articular and growth plate cartilage where Sox9 is known to be expressed, but also in the primary spongiosa, periosteum, and endosteum. RNA sequencing and subsequent analysis showed that Td-Tomato positive periosteal cells were enriched in Sox9 transcripts, and transcripts for various osteogenic and chondrocyte specific genes. In a femoral fracture model, we showed that pre-labeled Td-Tomato positive descendent cells were mobilized during the fracture repair process, expanding and migrating towards the fracture site 3 days post-fracture. Here, Td-Tomato positive cells differentiate into chondrocytes and osteoblasts in the soft and hard callus, respectively, 9 days post-fracture. By 2 months post-fracture, descendants of the original Sox9 labelled cell population were prevalent in the cortex and periosteum, and amongst the differentiated osteocyte population embedded within the cortical bone. Thus, a Sox9+ progenitor population resides in the adult periosteum. Fate tracing shows that these cells likely play a substantial role in repair of the fractured femur giving rise to chondrocytes, osteoblasts and mature cortical osteocytes. To our knowledge this is the first report of this Sox9+ cell population in the periosteum of the adult long bone. Taken together with developmental studies on skeletal formation, our data suggest that Sox9+ osteochondroprogenitors play a continuous role in skeletal formation throughout life.

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Mapping Somatosensory Afferent Circuitry to Bone Identifies Neurotrophic Signals Required for Fracture Healing

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