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

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 frontal bone of the calvaria at E8.5, E9, E9.5, E10, E10.5, E11, E11.5, E12, E12.5, E13.5 and E14.5