CROSSBONE · Decisive early crosstalk in bone repair: vessel, nerve and stem cell interactions in healthy and Neurofibromatosis type 1 conditions

Bone fractures are common traumatic injuries and a significant global health challenge. Successful healing depends on skeletal stem progenitor cells (SSPCs) producing cartilage and bone via a complex process. New vessel and nerve formations in the bone microenvironment are also crucial to determine the healing outcome. When disrupted, bone healing is impaired and fibrosis emerges, impacting patients’ life. In current research on bone repair disorders, there is a lack of understanding of initial triggers influencing cell differentiation and healing outcomes. In Neurofibromatosis type 1 (NF1), the host laboratory identified an early SSPC shift from a chondrogenic fate to a fibrotic fate promoting fibrosis instead of bone formation. Analysing the factors causing this cell fate shift is essential to understand altered mechanisms in pathological conditions. CROSSBONE will address these needs by unveiling the SSPC niche initial regulatory mechanisms influencing bone healing and fibrosis. It will analyse healthy fracture healing, detailing angiogenesis, reinnervation and SSPC interactions. Then I will investigate NF1 pathological mechanisms, focusing on this crosstalk and how it can disrupt healing. The project will use complementary in vitro and in vivo experiments, single-cell transcriptomics, and advanced tools to dissect spatial-temporal crosstalk after fractures. These interdisciplinary methodologies will provide a comprehensive understanding of bone healing in healthy and pathological conditions. CROSSBONE will enhance my professional development, boosting independence and competitiveness for my future career. The findings will potentially impact the management of diseases where fibrosis influences bone healing, benefiting scientists, clinicians and patients in related fields. Integrating various disciplines and techniques, CROSSBONE aims to contribute pioneering insights into bone healing and fibrosis, supporting new therapeutic strategies.