Human vascularised mesenchymal spheroids highlight the role of WDR35 in bone formation

Abstract

Background & Aim Early steps of bone formation rely on the condensation of multipotent mesenchymal stromal cells (MSC) towards osteogenesis associating with angiogenesis self-organization. However, the molecular mechanisms remain incompletely understood. Methods, Results & Conclusion For the first time, we developed a human 3D spheroid model from immature bone marrow MSC that spontaneously commit to osteoblast lineage and sustain a CD31+ endothelial network surrounded by aSMA+ cells. At a functional level, in vivo, subcutaneous spheroids implantation in immunodeficient chimeric mice leads to human bone marrow cavities genesis. Interestingly, through a GSEA analysis, we observed a good correlation (p≤0.0001) by comparing this 3D model to our previous results, where the skeletogenic master gene DLX5 is overexpressed. Among the most correlated genes, we found WDR35 a mutated gene in congenital skeletal ciliopathies which underline its crucial role in bone formation. These results also indicate that these mesenchymal vascularised spheroids could be relevant models to study human pathological bone development.