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This study was undertaken to design and test a self\u2010assembled skin equivalent (saSE) system that recapitulates the cross\u2010talk between macrophages and fibroblasts in cutaneous fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>SSc\u2010derived dermal fibroblasts (SScDFs) and normal dermal fibroblasts (NDFs) were cultured with CD14+ monocytes from SSc patients or healthy controls to allow de novo stroma formation. Monocyte donor\u2013matched plasma was introduced at week 3 prior to seeding keratinocytes to produce saSE with a stratified epithelium. Tissue was characterized by immunohistochemical staining, atomic force microscopy, enzyme\u2010linked immunosorbent assay, and quantitative reverse transcriptase\u2013polymerase chain reaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Stroma synthesized de novo from NDFs and SScDFs supported a fully stratified epithelium to form saSE. A thicker and stiffer dermis was generated by saSE with SScDFs, and more interleukin\u20106 and transforming growth factor \u03b2 (TGF\u03b2) was secreted by saSE with SScDFs compared to saSE with NDFs, regardless of the inclusion of monocytes. Tissue with SSc monocytes and plasma had amplified dermal thickness and stiffness relative to control tissue. Viable CD163+ macrophages were found within the stroma of saSE 5\u2009weeks after seeding. Additionally, SSc saSE contained greater numbers of CD163+ and CD206+ macrophages compared to control saSE. TGF\u03b2 blockade inhibited stromal stiffness to a greater extent in SSc saSE compared to control saSE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data suggest reciprocal activation between macrophages and fibroblasts that increases tissue thickness and stiffness, which is dependent in part on TGF\u03b2 activation. The saSE system may serve as a platform for preclinical therapeutic testing and for molecular characterization of SSc skin pathology through recapitulation of the interactions between macrophages and fibroblasts.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42097","type":"journal-article","created":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T03:54:01Z","timestamp":1645761241000},"page":"1245-1256","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Self\u2010Assembled Human Skin Equivalents Model Macrophage Activation of Cutaneous Fibrogenesis in Systemic Sclerosis"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1675-8575","authenticated-orcid":false,"given":"Mengqi","family":"Huang","sequence":"first","affiliation":[{"name":"Dartmouth Geisel School of Medicine, Hanover, New Hampshire, and University of Pittsburgh  Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avi","family":"Smith","sequence":"additional","affiliation":[{"name":"Tufts University  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Watson","sequence":"additional","affiliation":[{"name":"Tufts University  Medford Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajan","family":"Bhandari","sequence":"additional","affiliation":[{"name":"Dartmouth Geisel School of Medicine  Hanover New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren M.","family":"Baugh","sequence":"additional","affiliation":[{"name":"Tufts University  Medford Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Ivanovska","sequence":"additional","affiliation":[{"name":"Celdara Medical LLC, Lebanon  New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trishawna","family":"Watkins","sequence":"additional","affiliation":[{"name":"Tufts University  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Lang","sequence":"additional","affiliation":[{"name":"Tufts University  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9550-7178","authenticated-orcid":false,"given":"Maria","family":"Trojanowska","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Lauren D.","family":"Black","sequence":"additional","affiliation":[{"name":"Tufts University  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia A.","family":"Pioli","sequence":"additional","affiliation":[{"name":"Dartmouth Geisel School of Medicine  Hanover New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Garlick","sequence":"additional","affiliation":[{"name":"Tufts University  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.","family":"Whitfield","sequence":"additional","affiliation":[{"name":"Dartmouth Geisel School of Medicine  Hanover New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,30]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102515"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2018.06.013"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39658"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27647"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1635114100"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.21894"},{"key":"e_1_2_8_8_1","unstructured":"LangI HuangM SmithA FinkelmanM WhitfieldML GarlickJ.Effect of scleroderma\u2010derived fibroblast passage number on 3D Self\u2010assembled tissues [poster]. 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