{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T08:17:43Z","timestamp":1787905063338,"version":"build-2784847793"},"reference-count":39,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,11,27]],"date-time":"2021-11-27T00:00:00Z","timestamp":1637971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UG3TR002136, R01 AR063713, R01 AR073145"],"award-info":[{"award-number":["UG3TR002136, R01 AR063713, R01 AR073145"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Ellenburg Chair in Surgery at Stanford University","award":["the Ellenburg Chair in Surgery at Stanford University"],"award-info":[{"award-number":["the Ellenburg Chair in Surgery at Stanford University"]}]},{"name":"Lee Quo Wei and Lee Yick Hoi Lun Professorship of The Chinese University of Hong Kong","award":["Lee Quo Wei and Lee Yick Hoi Lun Professorship of The Chinese University of Hong Kong"],"award-info":[{"award-number":["Lee Quo Wei and Lee Yick Hoi Lun Professorship of The Chinese University of Hong Kong"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fibroblasts in the synovial membrane secrete molecules essential to forming the extracellular matrix (ECM) and supporting joint homeostasis. While evidence suggests that fibroblasts contribute to the response to joint injury, the outcomes appear to be patient-specific and dependent on interactions between resident immune cells, particularly macrophages (M\u03c6s). On the other hand, the response of M\u03c6s to injury depends on their functional phenotype. The goal of these studies was to further explore these issues in an in vitro 3D microtissue model that simulates a pathophysiological disease-specific microenvironment. Two sources of fibroblasts were used to assess patient-specific influences: mesenchymal stem cell (MSC)- and induced pluripotent stem cell (iPSC)-derived fibroblasts. These were co-cultured with either M1 or M2 M\u03c6s, and the cultures were challenged with polyethylene particles coated with lipopolysaccharide (cPE) to model wear debris generated from total joint arthroplasties. Our results indicated that the fibroblast response to cPE was dependent on the source of the fibroblasts and the presence of M1 or M2 M\u03c6s: the fibroblast response as measured by gene expression changes was amplified by the presence of M2 M\u03c6s. These results demonstrate that the immune system modulates the function of fibroblasts; furthermore, different sources of differentiated fibroblasts may lead to divergent results. Overall, our research suggests that M2 M\u03c6s may be a critical target for the clinical treatment of cPE induced fibrosis.<\/jats:p>","DOI":"10.3390\/ijms222312837","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T23:22:28Z","timestamp":1638314548000},"page":"12837","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Macrophages Modulate the Function of MSC- and iPSC-Derived Fibroblasts in the Presence of Polyethylene Particles"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0175-566X","authenticated-orcid":false,"given":"Qi","family":"Gao","sequence":"first","affiliation":[{"name":"Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6009-629X","authenticated-orcid":false,"given":"Zhong","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Rhee","sequence":"additional","affiliation":[{"name":"Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqi","family":"Xiang","sequence":"additional","affiliation":[{"name":"Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elijah Ejun","family":"Huang","sequence":"additional","affiliation":[{"name":"Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Yao","sequence":"additional","affiliation":[{"name":"Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6196-3722","authenticated-orcid":false,"given":"Bruce A.","family":"Bunnell","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6067-6705","authenticated-orcid":false,"given":"Rocky S.","family":"Tuan","sequence":"additional","affiliation":[{"name":"Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"},{"name":"Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Lin","sequence":"additional","affiliation":[{"name":"Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Gold","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart B.","family":"Goodman","sequence":"additional","affiliation":[{"name":"Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16469","DOI":"10.1038\/srep16469","article-title":"Fibrosis is a common outcome following total knee arthroplasty","volume":"5","author":"Abdul","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nrm3904","article-title":"Remodelling the extracellular matrix in development and disease","volume":"15","author":"Bonnans","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1093\/rheumatology\/kev228","article-title":"Unravelling osteoarthritis-related synovial fibrosis: A step closer to solving joint stiffness","volume":"54","author":"Remst","year":"2015","journal-title":"Rheumatology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Hodgeson, S., O\u2019Brien, S., Simkin, J., Plakotaris, E., McCarthy, C., Dasa, V., and Marrero, L. (2021). Differences in synovial fibrosis relative to range of motion in knee osteoarthritis patients. J. Orthop. Res., 1\u201311.","DOI":"10.1002\/jor.25061"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3928\/01477447-20130327-34","article-title":"Severe persistent synovitis after cobalt-chromium total knee arthroplasty requiring revision","volume":"36","author":"Thakur","year":"2013","journal-title":"Orthopedics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1093\/rheumatology\/keh344","article-title":"Osteoarthritis, angiogenesis and inflammation","volume":"44","author":"Bonnet","year":"2005","journal-title":"Rheumatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13287-020-01885-3","article-title":"Synovial membrane mesenchymal stem cells: Past life, current situation, and application in bone and joint diseases","volume":"11","author":"Li","year":"2020","journal-title":"Stem Cell Res. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"30330","DOI":"10.1039\/C8RA04661A","article-title":"Characteristics of wear particles and wear behavior of retrieved PEEK-on-HXLPE total knee implants: A preliminary study","volume":"8","author":"Meng","year":"2018","journal-title":"RSC Adv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1098\/rsif.2008.0142","article-title":"The combined role of wear particles, macrophages and lymphocytes in the loosening of total joint prostheses","volume":"5","author":"Revell","year":"2008","journal-title":"J. R. Soc. Interface"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13018-019-1119-8","article-title":"Macrophage inhibits the osteogenesis of fibroblasts in ultrahigh molecular weight polyethylene (UHMWPE) wear particle-induced osteolysis","volume":"14","author":"Lei","year":"2019","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.immuni.2016.02.015","article-title":"Macrophages in Tissue Repair, Regeneration, and Fibrosis","volume":"44","author":"Wynn","year":"2016","journal-title":"Immunity"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1159\/000445096","article-title":"Fibroblasts and Mesenchymal Stromal\/Stem Cells Are Phenotypically Indistinguishable","volume":"136","author":"Denu","year":"2016","journal-title":"Acta Haematol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.actbio.2020.11.017","article-title":"Engineering a cell-hydrogel-fibre composite to mimic the structure and function of the tendon synovial sheath","volume":"119","author":"Imere","year":"2021","journal-title":"Acta Biomater."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"512","DOI":"10.3389\/fimmu.2020.00512","article-title":"Versican\u2014A Critical Extracellular Matrix Regulator of Immunity and Inflammation","volume":"11","author":"Wight","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ortiz-Vitali, J.L., and Darabi, R. (2019). iPSCs as a Platform for Disease Modeling, Drug Screening, and Personalized Therapy in Muscular Dystrophies. Cells, 8.","DOI":"10.3390\/cells8010020"},{"key":"ref_16","first-page":"139","article-title":"Patient-Specific iPSC-Based Disease Model for Pathogenesis Studies and Clinical Pharmacotherapy","volume":"176","author":"Li","year":"2016","journal-title":"Physiol. Behav."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.stem.2020.02.011","article-title":"Multi-lineage Human iPSC-Derived Platforms for Disease Modeling and Drug Discovery","volume":"26","author":"Sharma","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1111\/wrr.12939","article-title":"Fibroblast-like synoviocytes: Role in synovial fibrosis associated with osteoarthritis","volume":"29","author":"Maglaviceanu","year":"2021","journal-title":"Wound Repair Regen."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Gao, Q., Rhee, C., Maruyama, M., Li, Z., Shen, H., Zhang, N., Utsunomiya, T., Huang, E.E., Yao, Z., and Bunnell, B.A. (2021). The effects of macrophage phenotype on osteogenic differentiation of mscs in the presence of polyethylene particles. Biomedicines, 9.","DOI":"10.3390\/biomedicines9050499"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2744","DOI":"10.1002\/jbm.a.36504","article-title":"NF\u03baB sensing IL-4 secreting mesenchymal stem cells mitigate the proinflammatory response of macrophages exposed to polyethylene wear particles","volume":"106","author":"Lin","year":"2018","journal-title":"J. Biomed. Mater. Res.-Part A"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1111\/liv.14390","article-title":"Collagen biology and non-invasive biomarkers of liver fibrosis","volume":"40","author":"Karsdal","year":"2020","journal-title":"Liver Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.2353\/ajpath.2007.070112","article-title":"The myofibroblast: One function, multiple origins","volume":"170","author":"Hinz","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.tranon.2018.11.004","article-title":"Serological Assessment of Activated Fibroblasts by alpha-Smooth Muscle Actin (\u03b1-SMA): A Noninvasive Biomarker of Activated Fibroblasts in Lung Disorders","volume":"12","author":"Willumsen","year":"2019","journal-title":"Transl. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.bbadis.2016.11.006","article-title":"The role of \u03b1-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling","volume":"1863","author":"Shinde","year":"2017","journal-title":"Biochim. Biophys. Acta-Mol. Basis Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1089\/scd.2013.0477","article-title":"Functional comparison of human-induced pluripotent stem cell-derived mesenchymal cells and bone marrow-derived mesenchymal stromal cells from the same donor","volume":"23","author":"Diederichs","year":"2014","journal-title":"Stem Cells Dev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3389\/fbioe.2019.00411","article-title":"Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs","volume":"7","author":"Lin","year":"2019","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1146\/annurev-cellbio-100109-104020","article-title":"Assembly of fibronectin extracellular matrix","volume":"26","author":"Singh","year":"2010","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1080\/19336918.2014.1000071","article-title":"Role of tenascins in the ECM of gliomas","volume":"9","author":"Faissner","year":"2015","journal-title":"Cell Adhes. Migr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.matbio.2012.11.003","article-title":"MiRNAs regulate expression and function of extracellular matrix molecules","volume":"32","author":"Rutnam","year":"2013","journal-title":"Matrix Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1302\/0301-620X.100B7.BJJ-2017-1590.R2","article-title":"Ceramic prosthesis surfaces induce an inflammatory cell response and fibrotic tissue changes","volume":"100B","author":"Bertrand","year":"2018","journal-title":"Bone Jt. J."},{"key":"ref_31","first-page":"86","article-title":"Macrophages and bone inflammation","volume":"10","author":"Gu","year":"2017","journal-title":"J. Orthop. Transl."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e000527","DOI":"10.1136\/rmdopen-2017-000527","article-title":"Synovial tissue macrophages: Friend or foe?","volume":"3","author":"Alivernini","year":"2017","journal-title":"RMD Open"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"568756","DOI":"10.3389\/fvets.2020.568756","article-title":"Macrophage Activation in the Synovium of Healthy and Osteoarthritic Equine Joints","volume":"7","author":"Menarim","year":"2020","journal-title":"Front. Vet. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1093\/intimm\/dxy054","article-title":"Macrophages in inflammation, repair and regeneration","volume":"30","author":"Oishi","year":"2018","journal-title":"Int. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Hesketh, M., Sahin, K.B., West, Z.E., and Murray, R.Z. (2017). Macrophage phenotypes regulate scar formation and chronic wound healing. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071545"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/s41577-021-00540-z","article-title":"Fibroblasts as immune regulators in infection, inflammation and cancer","volume":"21","author":"Davidson","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s12964-018-0300-8","article-title":"M2 macrophages promote myofibroblast differentiation of LR-MSCs and are associated with pulmonary fibrogenesis 11 Medical and Health Sciences 1102 Cardiorespiratory Medicine and Haematology","volume":"16","author":"Hou","year":"2018","journal-title":"Cell Commun. Signal."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"L14","DOI":"10.1152\/ajplung.00400.2018","article-title":"Tgf-\u03b2 activation impairs fibroblast ability to support adult lung epithelial progenitor cell organoid formation","volume":"317","author":"Kortekaas","year":"2019","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1089\/ten.tea.2013.0642","article-title":"Cartilage tissue engineering application of injectable gelatin hydrogel with in situ visible-light-activated gelation capability in both air and aqueous solution","volume":"20","author":"Lin","year":"2014","journal-title":"Tissue Eng. Part A"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/12837\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:36:43Z","timestamp":1760168203000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/12837"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,27]]},"references-count":39,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ijms222312837"],"URL":"https:\/\/doi.org\/10.3390\/ijms222312837","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,27]]}}}