PMID- 32697440 OWN - NLM STAT- MEDLINE DCOM- 20210831 LR - 20240330 IS - 2157-6580 (Electronic) IS - 2157-6564 (Print) IS - 2157-6564 (Linking) VI - 9 IP - 12 DP - 2020 Dec TI - Human perivascular stem cells prevent bone graft resorption in osteoporotic contexts by inhibiting osteoclast formation. PG - 1617-1630 LID - 10.1002/sctm.20-0152 [doi] AB - The vascular wall stores mesenchymal progenitor cells which are able to induce bone regeneration, via direct and paracrine mechanisms. 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. CI - (c) 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press. FAU - Negri, Stefano AU - Negri S AUID- ORCID: 0000-0003-2218-6654 AD - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. AD - Orthopaedic and Trauma Surgery Unit, Department of Surgery, Dentistry, Paediatrics and Gynaecology of the University of Verona, Verona, Italy. FAU - Wang, Yiyun AU - Wang Y AUID- ORCID: 0000-0003-0775-4377 AD - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. FAU - Sono, Takashi AU - Sono T AD - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. FAU - Lee, Seungyong AU - Lee S AD - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. FAU - Hsu, Ginny Ching-Yun AU - Hsu GC AD - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. FAU - Xu, Jiajia AU - Xu J AD - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. FAU - Meyers, Carolyn A AU - Meyers CA AD - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. FAU - Qin, Qizhi AU - Qin Q AD - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. FAU - Broderick, Kristen AU - Broderick K AD - Department of Plastic Surgery, Johns Hopkins University, Baltimore, Maryland, USA. FAU - Witwer, Kenneth W AU - Witwer KW AD - Departments of Molecular and Comparative Pathobiology and Neurology, Johns Hopkins University, Baltimore, Maryland, USA. FAU - Peault, Bruno AU - Peault B AD - UCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, Los Angeles, California, USA. AD - Center for Cardiovascular Science and MRC Center for Regenerative Medicine, University of Edinburgh, Edinburgh, UK. FAU - James, Aaron W AU - James AW AD - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. LA - eng GR - K08 AR068316/AR/NIAMS NIH HHS/United States GR - G1000816/MRC_/Medical Research Council/United Kingdom GR - CGA/18/33/CSO_/Chief Scientist Office/United Kingdom GR - R01 AR070773/AR/NIAMS NIH HHS/United States GR - R21 DE027922/DE/NIDCR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20200722 PL - England TA - Stem Cells Transl Med JT - Stem cells translational medicine JID - 101578022 SB - IM MH - Animals MH - Bone Resorption/*prevention & control MH - Female MH - Humans MH - Osteoclasts/*pathology MH - Osteoporosis/*physiopathology MH - Rats MH - Rats, Nude MH - Stem Cell Transplantation/*methods MH - Stem Cells/*metabolism MH - Transcriptome/*physiology PMC - PMC7695633 OTO - NOTNLM OT - adipose stem cell OT - bone graft OT - mesenchymal stem cell OT - osteoclast OT - pericyte OT - perivascular stem cell OT - spine fusion COIS- Bruno Peault is the inventor of perivascular stem cell related patents held by the UC Regents. Aaron W. James is a paid consultant for Novadip, and receives funding for unrelated research from MTF Biologics and Novadip. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Kristen Broderick declared advisory role with Margin Probe. The other authors delared no potential conflicts of interest. EDAT- 2020/07/23 06:00 MHDA- 2021/09/01 06:00 PMCR- 2020/07/22 CRDT- 2020/07/23 06:00 PHST- 2020/04/13 00:00 [received] PHST- 2020/05/24 00:00 [revised] PHST- 2020/06/15 00:00 [accepted] PHST- 2020/07/23 06:00 [pubmed] PHST- 2021/09/01 06:00 [medline] PHST- 2020/07/23 06:00 [entrez] PHST- 2020/07/22 00:00 [pmc-release] AID - SCT312781 [pii] AID - 10.1002/sctm.20-0152 [doi] PST - ppublish SO - Stem Cells Transl Med. 2020 Dec;9(12):1617-1630. doi: 10.1002/sctm.20-0152. Epub 2020 Jul 22.