内皮化骨痂类器官驱动临界尺寸节段性长骨缺损的快速再生

摘要(中文译文)

大块骨缺损仍然是一个重大的临床挑战，因为当前的治疗方法无法有效使其再生，也未能恢复功能。为重现早期骨折骨痂的细胞复杂性，我们通过将骨膜来源的骨骼祖细胞与内皮细胞共培养，工程化构建了人源内皮化骨痂类器官（hECOs）。这种共培养导致细胞自组装，形成空间有序的、类似骨痂的结构。内皮细胞促进了骨骼祖细胞扩增、细胞外基质成熟以及向肥大软骨的进展，这些都是软骨内成骨的标志。多组学分析鉴定出内皮细胞介导的再生程序激活，这些程序与骨骼成熟、基质重塑和血管生成相关。经过短暂的体外分化后，hECOs的宏观聚集体支持了免疫功能缺陷小鼠中宿主血管的快速长入和临界尺寸胫骨缺损的再生。供体来源细胞积极参与了早期再生，但在重塑过程中逐渐被替代，这与hECOs作为瞬态生物模板、引导宿主介导的骨再生相一致。

Abstract

Large bone defects remain a major clinical challenge, as current treatments cannot effectively regenerate them and fail to restore functionality. To recapitulate the cellular complexity of the early fracture callus, we engineered human endothelialized callus organoids (hECOs) by co-culturing periosteum-derived skeletal progenitors with endothelial cells. This co-culture resulted in cellular self-assembly, leading to spatially organized, callus-like structures. Endothelial cells promoted skeletal progenitor cell expansion, extracellular matrix maturation, and progression toward hypertrophic cartilage, hallmarks of endochondral ossification. Multi-omics analyses identified endothelial cell-mediated activation of regenerative programs associated with skeletal maturation, matrix remodeling, and angiogenesis. Following brief in vitro differentiation, macroscale aggregates of hECOs supported rapid host vascularization and regeneration of critical-size tibial defects in immunocompromised mice. Donor-derived cells actively contributed to early regeneration but were progressively replaced during remodeling, consistent with hECOs functioning as transient biological templates that guide host-mediated bone regeneration.

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