Department of Pathology, Johns Hopkins University, Baltimore, United States
Yiyun Wang
Department of Pathology, Johns Hopkins University, Baltimore, United States
Ching-Yun Hsu
Department of Pathology, Johns Hopkins University, Baltimore, United States
Yongxing Gao
Department of Pathology, Johns Hopkins University, Baltimore, United States
Carolyn Ann Meyers
Department of Pathology, Johns Hopkins University, Baltimore, United States
Leslie Chang
Department of Pathology, Johns Hopkins University, Baltimore, United States
Leititia Zhang
Department of Pathology, Johns Hopkins University, Baltimore, United States; Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, China
Kristen Broderick
Department of Surgery, Johns Hopkins University, Baltimore, United States
Catherine Ding
Department of Orthopaedic Surgery, Orthopaedic Hospital Research Center, UCLA, Orthopaedic Hospital, Los Angeles, United States
Bruno Peault
Department of Orthopaedic Surgery, Orthopaedic Hospital Research Center, UCLA, Orthopaedic Hospital, Los Angeles, United States; Centre For Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
Kenneth Witwer
Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, United States; Department of Neurology, Johns Hopkins University, Baltimore, United States
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.
