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The vascular wall is a source of progenitor cells that are able to induce skeletal repair, primarily by paracrine mechanisms. Here, the paracrine role of extracellular vesicles (EVs) in bone healing was investigated. First, purified human perivascular stem cells (PSCs) were observed to induce mitogenic, pro-migratory, and pro-osteogenic effects on osteoprogenitor cells while in non-contact co-culture via elaboration of EVs. PSC-derived EVs shared mitogenic, pro-migratory, and pro-osteogenic properties of their parent cell. PSC-EV effects were dependent on surface-associated tetraspanins, as demonstrated by EV trypsinization, or neutralizing antibodies for CD9 or CD81. Moreover, shRNA knockdown in recipient cells demonstrated requirement for the CD9/CD81 binding partners IGSF8 and PTGFRN for EV bioactivity. Finally, PSC-EVs stimulated bone repair, and did so via stimulation of skeletal cell proliferation, migration, and osteodifferentiation. In sum, PSC-EVs mediate the same tissue repair effects of perivascular stem cells, and represent an ‘off-the-shelf’ alternative for bone tissue regeneration., eLife digest Throughout our lives, our bodies need to heal after injury. Blood vessels are found throughout the body’s tissues and are a source of cells that guide the process of repair. These cells, called perivascular stem cells (PSCs), are a type of stem cell found in the lining of blood vessels. Stem cells are cells that can become one of several different types of mature cells, depending on what the body needs. Extracellular vesicles are bundles of chemical signals that cells send into their external environment. Just like an address or a tag on a parcel, specific molecules mark the exterior surface of these bundles to deliver the message to the right recipient. Stem cells often use extracellular vesicles to communicate with surrounding cells. One role of PSCs is repairing damage to bones. Unusually, they do not turn into new bone cells and so do not directly contribute to the re-growing tissue. Instead, PSCs act indirectly, by stimulating the cells around them. How PSCs send these ‘repair instructions’ has, however, remained unclear. Xu et al. wanted to determine if PSCs used extracellular vesicles to direct bone repair, and if so, what ‘tags’ needed to be on the vesicles and on the receiving cells for this to happen. Experiments using PSCs and immature bone cells grown in the laboratory allowed the PSCs’ effect on bone cells to be simulated in a Petri dish. The two types of cells were grown on either side of a barrier, which separated them physically but allowed chemical signals through. In response to the PSCs, the immature bone cells multiplied, started to move (which is something they need to do to heal damaged tissue), and began to resemble mature bone cells. Analysis of the signals released by the PSCs revealed that these were indeed extracellular vesicles, and that they were tagged by specific proteins called tetraspanins. Genetic manipulation of the immature bone cells later showed that these cells needed specific ‘receiver’ molecules to respond to the PSCs. Adding only extracellular vesicles to the bone cells, without any PSCs, confirmed that it was indeed the vesicles that triggered the healing response. Finally, giving the vesicles to mice with bone damage helped them to heal faster than untreated animals. These results have uncovered a key mechanism by which stem cells control the repair of bone tissue. This could one day lead to better treatments for patients recovering from fractures or needing bone surgery.