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Although much is known regarding perivascular cell regulation of osteoblasts, their regulation of osteoclasts, and by extension utility in states of high bone resorption, is not known. Here, human perivascular stem cells (PSCs) were used as a means to prevent autograft resorption in a gonadectomy-induced osteoporotic spine fusion model. Furthermore, the paracrine regulation by PSCs of osteoclast formation was evaluated, using coculture, conditioned medium, and purified extracellular vesicles. Results showed that PSCs when mixed with autograft bone induce an increase in osteoblast:osteoclast ratio, promote bone matrix formation, and prevent bone graft resorption. The confluence of these factors resulted in high rates of fusion in an ovariectomized rat lumbar spine fusion model. Application of PSCs was superior across metrics to either the use of unpurified, culture-defined adipose-derived stromal cells or autograft bone alone. Under coculture conditions, PSCs negatively regulated osteoclast formation and did so via secreted, nonvesicular paracrine factors. Total RNA sequencing identified secreted factors overexpressed by PSCs which may explain their negative regulation of graft resorption. In summary, PSCs reduce osteoclast formation and prevent bone graft resorption in high turnover states such as gonadectomy-induced osteoporosis.<\/jats:p><jats:sec><jats:title\/><jats:p>Significance statement Perivascular progenitor cells exert positive regulatory effects on osteoblasts to heal bones, yet their potential role in osteoclast regulation is not known. It is observed that human perivascular progenitor cells reduce osteoclast formation, thereby preventing bone graft resorption and yielding better outcomes in a preclinical xenograft model. In the future, perivascular stem cells could be used to augment bone grafts, serving as a pro-anabolic, antiosteoclastic stimulus for better outcomes in orthopaedics.<\/jats:p><\/jats:sec>","DOI":"10.1002\/sctm.20-0152","type":"journal-article","created":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T14:50:54Z","timestamp":1595429454000},"page":"1617-1630","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Human perivascular stem cells prevent bone graft resorption in osteoporotic contexts by inhibiting osteoclast formation"],"prefix":"10.1093","volume":"9","author":[{"given":"Stefano","family":"Negri","sequence":"first","affiliation":[{"name":"1 Department of Pathology Johns Hopkins University, Baltimore, Maryland, USA"},{"name":"2 Orthopaedic and Trauma Surgery Unit, Department of Surgery, Dentistry Paediatrics and Gynaecology of the University of Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyun","family":"Wang","sequence":"additional","affiliation":[{"name":"1 Department of Pathology Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Sono","sequence":"additional","affiliation":[{"name":"1 Department of Pathology Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seungyong","family":"Lee","sequence":"additional","affiliation":[{"name":"1 Department of Pathology Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginny Ching-Yun","family":"Hsu","sequence":"additional","affiliation":[{"name":"1 Department of Pathology Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Xu","sequence":"additional","affiliation":[{"name":"1 Department of Pathology Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn A.","family":"Meyers","sequence":"additional","affiliation":[{"name":"1 Department of Pathology Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qizhi","family":"Qin","sequence":"additional","affiliation":[{"name":"1 Department of Pathology Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Broderick","sequence":"additional","affiliation":[{"name":"3 Department of Plastic Surgery Johns Hopkins University, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth 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