Nat Commun. 2025 Jul 4;16(1):6200. doi: 10.1038/s41467-025-61619-y.

ABSTRACT

Current approaches for bone repair predominantly target localized delivery of growth factors that are aimed at the coupling of angiogenesis and osteogenesis. However, delayed revascularization and regeneration of critical-sized bone defects are still challenging. In this study, we engineer an ossification center-like organoid (OCO) that consist of an inner-core bone morphogenetic and neurotrophic spheroid generated via MSCs-loaded 3D printing, alongside the interstitially distributed outer-shell proangiogenic neurotrophic phase. Our results demonstrate that collective implantation of OCOs achieves rapid bone bridging with successive OC-like bone ossicles formation across the bone defect in a « divide-and-conquer » way. Single-cell RNA sequencing analysis unveils a developmentally mimicking stem cell community that dominated with Krt8+ skeletal stem cells (SSCs) is uniquely recruited by the pro-regenerative in-situ organoid fusion and maturation. Particularly noteworthy is the specific expansion of Krt8+ SSCs concomitant with the simultaneous reduction of Has1+ migratory fibroblasts (MFs) post-OCO implantation. Furthermore, cross-species comparisons employing machine learning reveal high resemblance of the relative Krt8+ SSCs/Has1+ MFs composition in bone regeneration with that in public data from developmental bone tissues. Our findings advocate an approach akin to « divide-and-conquer » utilizing engineered OC-like organoids for prompt regeneration of large-sized bone defects.

PMID:40615395 | DOI:10.1038/s41467-025-61619-y