CE14 - Physiologie et physiopathologie

Target skeletal stem cells in periosteum for skeletal regeneration and diseases – PERISTEM

Submission summary

Musculoskeletal diseases and disorders affect 1 in 7 people and represent the second cause of disability worldwide. Impaired bone healing can be associated with severe trauma, osteonecrosis, tumour resection and bone diseases. The societal cost of these repair delays is very high due to heavy surgeries and rehabilitation. In France the cost can be estimated over 600 millions euros per year with additional costs due to permanent sequelae, long-term medical follow-up and patient disability. A significant challenge for orthopaedic surgeons is to reduce and realign bone fractures or fill large defects that fail to heal. Tremendous efforts are being made worldwide to develop cell-based therapy with bone marrow stromal/skeletal stem cells (BMSCs) without frank success to efficiently repair diseased or damaged bone. The poor survival and long-term integration of transplanted BMSCs are major limitations. There is a large gap of knowledge in this field and we aim to fill this gap through stem cell research with great potential for application in skeletal diseases and traumatology.

We showed that periosteum, the tissue lining the outer surface of bone, is a key component of bone repair and contains skeletal stem cells with higher bone regenerative potential compared to bone marrow. However, little is known about the role of periosteum in bone repair disorders. The PERISTEM project aims to enhance musculoskeletal regeneration by understanding the biology of skeletal stem cells in periosteum during the physiological response to bone injury and in congenital pseudarthrosis of the tibia (CPT), as a model of pathological bone repair. CPT is a severe paediatric orthopaedic condition characterized by bone deformities and weakness leading to spontaneous fractures and pseudarthrosis (i.e. absence of bone healing). More than 50% of CPT cases are diagnosed in patients with type 1 neurofibromatosis (NF1), a complex genetic disorder linked to mutations in the NF1 gene, encoding the tumour suppressor RAS-GTPase-activating protein neurofibromin. NF1 mutations cause constitutive activation of several signalling pathways including RAS-ERK pathway and a wide spectrum of phenotypic manifestations with variable severity such as neurofibromas, learning disabilities, vision and bone disorders with no genotype-phenotype correlation and no effective treatment options reported so far.

The PERISTEM project will determine the extent to which periosteum deficiencies and impaired interactions between bone and the peripheral nervous system cause the bone repair deficit in CPT. First, we will characterize the impact of NF1 loss of function in the skeletal lineage within periosteum in mouse models and in NF1 patient samples. Second, we will assess effects of NF1 loss of function in neural crest cell derivatives in a new mouse model of NF1 that recapitulate many aspects of NF1 pathology including deficient bone repair. Third, we will apply this knowledge to bone repair in general by enhancing the regenerative potential of PCs pharmacologically and developing cell-based approaches using PCs as a more promising and efficient alternative to BMSCs. This collaborative project brings together 3 partners with complementary expertise in bone biology and repair (Partner 1), molecular genetic and physiopathology in NF1 (Partner 2), peripheral nerve and stem cell biology (Partner 3).

Project coordinator

Madame Celine Colnot (Institut Mondor de Recherche Biomédicale)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IMRB Institut Mondor de Recherche Biomédicale
IMRB Institut Mondor de Recherche Biomédicale
EA 7331 GÉNÉTIQUE, PHYSIOPATHOLOGIE ET APPROCHES THÉRAPEUTIQUES DES MALADIES HÉRÉDITAIRES DU SYSTÈME NERVEUX

Help of the ANR 435,039 euros
Beginning and duration of the scientific project: December 2018 - 48 Months

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