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 trauma, resection of bone tumors, osteonecrosis and severe 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.
1-Role of skeletal stem cells in periosteum
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 focus on the role of the periosteum, the tissue that lies at the outer surface of bone.
We showed that skeletal stem/progenitors from periosteum and bone marrow are derived from a common mesenchymal lineage during development but acquire distinct properties in adult bone. Skeletal stem/progenitors from periosteum exhibit higher bone regenerative potential compared to bone marrow stromal cells. The extracellular matrix composition of the periosteum also plays essential roles in periosteum functions and we identified that the matricellular protein Periostin regulates the activation of skeletal stem/progenitors in response to bone injury and their long-term maintenance within periosteum.
In mice carrying the Fgfr3Y367C activating mutation in Prx1-derived skeletal stem/progenitor cells, we observed a severe bone repair phenotype associated with pseudarthrosis. This phenotype is due to functional impairment of periosteal cells in mediating cartilage to bone transformation thus uncovering an essential role of periosteal cells in bone healing.
2-Role of muscle-bone interactions in musculoskeletal regeneration
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.
Genetic disorders affecting muscle such as Duchenne Muscular Dystrophy (DMD) also impact bone and we have shown that bone regeneration is deficient in a mouse model of DMD. Similarly, loss of bone quality in osteoporosis is linked with sarcopenia. However, the biological mechanisms underlying the role of muscle in bone repair remain poorly understood.
We showed that muscle stem cells, the satellite cells, play a role in skeletal regeneration via paracrine effects of secreted factors in response to bone injury.
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 also become pro-fibrotic in the context of musculoskeletal trauma, a process that can be targeted pharmacologically to improve bone repair.