Abstract
Emerging evidence suggests that extracellular vesicles (EVs) are secreted by diverse tissues and play important roles in cell-cell communication, organ interactions and tissue homeostasis. Studies have reported the use of EVs to stimulate tissue regeneration, such as hepatic cell regeneration, and to treat diseases, such as pulmonary hypertension. However, little is known about the osteogenic effect of EVs. In this study, we explore the role of bone marrow stromal cell-derived EVs in the regulation of osteoblast activity and bone regeneration. We isolated bone marrow stromal/stem cell (BMSC)-derived EVs through gradient ultracentrifugation and ultrafiltration, and tested the influence of the EVs on osteogenesis both in vivo and in vitro. The results indicated that EVs positively regulated osteogenic genes and osteoblastic differentiation but did not inhibit proliferation in vitro. Furthermore, we constructed an EVs delivery system to stimulate bone formation in Sprague Dawley (SD) rats with calvarial defects. We found that BMSC-derived EVs led to more bone formation in the critical-size calvarial bone defects. Moreover, we found that miR-196a plays an essential role in the regulation of osteoblastic differentiation and the expression of osteogenic genes. We anticipate that our assay using bone marrow stromal cell-derived EVs will become a valuable tool for promoting bone regeneration.
Highlights
Hepatic stellate cell-derived Extracellular vesicles (EVs) inhibit hepatic fibrosis[15] and mesenchymal stromal cell-derived EVs stimulate tissue resident stem cells, restoring the integrity and functionality of tissues[16]
Our results show that human BMSC-derived EVs can enter the osteoblasts and deliver osteogenic miRNAs by endocytosis, modulating osteogenic gene expression and differentiation in vitro
To explore the tentative involvement of BMSCs in the recovery of bone defects in vivo, we first examined whether BMSCconditioned medium (BM) could stimulate osteoblastic differentiation
Summary
Hepatic stellate cell-derived EVs inhibit hepatic fibrosis[15] and mesenchymal stromal cell-derived EVs stimulate tissue resident stem cells, restoring the integrity and functionality of tissues[16]. Large bone defects are a common, debilitating clinical condition[17]. Earlier studies based on animal models have suggested that local transplantation of BMSCs promote bone regeneration through unknown mechanisms[18]. BMSCs actively produce EVs, and BMSC-conditioned medium potently stimulates bone regeneration[19]. The potential role of BMSC-derived EVs in bone regeneration is unclear, and the possible underlying mechanisms have yet to be determined. We collected and isolated BMSCs from clinic. We examined the tentative role of EVs in bone regeneration and interrogated the underlying mechanisms. Our results show that human BMSC-derived EVs can enter the osteoblasts and deliver osteogenic miRNAs by endocytosis, modulating osteogenic gene expression and differentiation in vitro. BMSC-derived EVs substantially promoted bone regeneration in SD rats with calvarial defects
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