Research focus
Stem cells in musculoskeletal development, regeneration and diseases
Musculoskeletal disorders affect 1 in 7 people (10 million people in Europe) and are the second cause of disability worldwide. Fractures due to genetic diseases, osteoporosis or trauma have a prevalence of 1 in 50 people affected annually. Large bone defects caused by severe trauma, resection of bone tumors, osteonecrosis and skeletal dysplasia represent significant clinical challenges, as bone does not regenerate spontaneously in these situations. In order to enhance musculoskeletal regeneration, our research concentrates on the role of skeletal stem cells in bone development, growth and regeneration in order to improve our understanding of skeletal repair defects both in children and adult, using genetic mouse models, genomics and cellular approaches.
Role of skeletal stem/progenitor cells in periosteum
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The process of bone formation begins during embryogenesis and continues throughout bone growth, homeostasis and aging, and during bone regeneration and repair. We study the ontogeny of skeletal stem cells, how they are established during the development and growth of the skeleton and how they are affected in genetic diseases and skeletal repair disorders. Skeletal stem cells have been identified in several bone compartments of the adult skeleton.
We showed that periosteum, the tissue lining the outer surface of bone, is a key component of bone repair and contains skeletal stem/progenitor cells (SSPCs) with higher bone regenerative potential compared to bone marrow (Duchamp de Lageneste et al., Nature Communications 2018). We developed scRNAseq and snRNAseq to elucidate the heterogeneity of SSPC populations and their response to injury. In response to fracture, periosteal SSPCs transition via an injury-induced fibrogenic phase prior to undergoing osteogenesis or chondrogenesis (Julien et al., JBMR 2022, Perrin et al. Elife 2024).
In our latest publication (Perrin et al, Science Translational Medicine, 2024), we investigated Congenital pseudarthrosis of the tibia (CPT), a severe pathology affecting children and characterized by spontaneous fractures that fail to heal. Half of patients with CPT are also diagnosed with the genetic disorder neurofibromatosis type 1 (NF1), caused by mutations in the NF1 gene. We uncovered that periosteal skeletal stem/progenitor cells and Schwann cells both carry NF1 biallelic inactivation in patients with CPT. We elucidated the mechanisms leading to the fibrotic fate of Nf1-deficient periosteal skeletal stem/progenitor cells. We identified the profibrotic role of Nf1-deficient Schwann cells in driving fibrotic accumulation in CPT via TGFβ and successfully tested a combination of MEK and SHP2 inhibitors to prevent fibrous nonunion in mice. This work opens new therapeutic perspectives for patients with CPT. It also provides very exciting new concepts on the role of the periosteum and Schwann cells in bone healing and fibrous nonunion.
​​Perrin et al., Elife 2024 Perrin et al., Science Translational Medicine, 2024
Role of muscle-bone interactions in musculoskeletal regeneration
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The recruitment of skeletal stem cells in bone defects or injuries occurs in an inflammatory environment and is influenced by environmental mechanical signals and the surrounding tissues such as muscle. Bone and skeletal muscle are closely linked across development, growth and aging. The delay in bone consolidation is increased up to 10-fold in patients with severe trauma to adjacent muscles.​
We showed that skeletal stem/progenitor cells that repair bone reside not only in bone compartments but also in skeletal muscle adjacent to bone. Cells recruited from skeletal muscle become pro-fibrotic in the context of musculoskeletal trauma, a process that can be targeted pharmacologically to improve bone repair (Julien et al., Nature Communications 2021; Julien et al., JBMR 2022).
Multimodal analyses of immune cells in bone repair
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Using single-nucleus transcriptomics, we generated an immune cell atlas of bone regeneration. Analyses uncovered parallel inflammatory responses of macrophages and skeletal stem progenitor cells in the early stages of bone healing. This coordinated process is disrupted in our mouse model of musculoskeletal trauma leading to fibrosis and impaired healing. We showed that modulating macrophage function decreased fibrosis and enhanced bone repair, revealing macrophages as a potential therapeutic target to treat trauma-associated fibrosis (Hachemi et al., Bone Research, 2024).
Immune cell atlas of bone repair
​​Hachemi, Perrin et al., Bone Research 2024