A bone regenerative strategy based on extracellular vesicles transporting citrate for promoting biomineralization [QH]

The mineralization of extracellular matrix (ECM) rich in collagen is a biological process in many bones. It is well known that organic molecules from the extracellular matrix of mineralized tissues are crucial for constructing apatite minerals. Here we found that differences in cellular metabolic status significantly affect the degree of mineralization. The metabolite citrate, as a component of apatite nanocomposites, is crucial to the biomineralization of bones. Citrate is transported to the ECM through extracellular vesicles (EVs) and amorphous calcium phosphate (ACPs). Functionally, citrate can bridge more Ca2+ in EVs, contributing to higher intra-fiber mineralization. EVs produced by cells with active metabolic levels can improve the mineralization of poorly mineralized cells. The results indicate that the content of EVs can reflect the metabolic state of cells, thereby regulating the function of ECM. In general, this work reveals the complex metabolic process as a way to regulate biomineralization and proposes a new form of molecular transport, which provides a new bio-inspired strategy for bone regeneration. Overall design: The mRNA profiles of mouse E14.5 frontal bone of the calvaria and parietal and inerparietal bone of the calvaria

富含胶原蛋白的细胞外基质（extracellular matrix, ECM）的矿化是诸多骨骼组织中普遍存在的生物学过程。众所周知，矿化组织细胞外基质中的有机分子对于磷灰石矿物的构建具有关键作用。本研究发现，细胞代谢状态的差异会显著影响矿化程度。作为磷灰石纳米复合材料的组分之一，代谢物柠檬酸（citrate）对骨骼的生物矿化过程至关重要。柠檬酸可通过细胞外囊泡（extracellular vesicles, EVs）与无定形磷酸钙（amorphous calcium phosphate, ACPs）被转运至细胞外基质。功能层面上，柠檬酸能够在细胞外囊泡中结合更多钙离子，从而促进纤维内矿化水平的提升。代谢活性旺盛的细胞所产生的细胞外囊泡，可改善矿化能力较弱的细胞的矿化过程。研究结果表明，细胞外囊泡的含量能够反映细胞的代谢状态，进而调控细胞外基质的功能。总体而言，本研究揭示了代谢过程可作为调控生物矿化的复杂途径，并提出了一种全新的分子转运模式，为骨再生领域提供了新型仿生策略。整体实验设计：对小鼠胚胎E14.5天颅盖骨的额骨、顶骨及顶间骨的mRNA表达谱进行检测分析。