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The bioengineered bilayered living cell construct (BLCC) is the only FDA\u2010approved therapy demonstrating efficacy in healing chronic VLU, yet its <jats:italic>in vivo<\/jats:italic> mechanisms of action are not well understood. Previously, we reported a BLCC\u2010mediated acute wounding response at the ulcer edge; in this study we elucidated the BLCC\u2010specific effects on the epidermis\u2010free ulcer bed. We conducted a randomized controlled clinical trial (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link> NCT01327937) enrolling 30 subjects with nonhealing VLUs, and performed genotyping, genomic profiling, and functional analysis on wound bed biopsies obtained at baseline and 1 week after treatment with BLCC plus compression or compression therapy (control). The VLU bed transcriptome featured processes of chronic inflammation and was strikingly enriched for fibrotic\/fibrogenic pathways and gene networks. BLCC application decreased expression of profibrotic TGF\u00df1 gene targets and increased levels of TGF\u00df inhibitor decorin. Surprisingly, BLCC upregulated metallothioneins and fibroblast\u2010derived MMP8 collagenase, and promoted endogenous release of MMP\u2010activating zinc to stimulate antifibrotic remodeling, a novel mechanism of cutaneous wound healing. By activating a remodeling program in the quiescent VLU bed, BLCC application shifts nonhealing to healing phenotype. As VLU bed fibrosis correlates with poor clinical healing, findings from this study identify the chronic VLU as a fibrotic skin disease and are first to support the development and application of antifibrotic therapies as a successful treatment approach.<\/jats:p>","DOI":"10.1111\/wrr.12778","type":"journal-article","created":{"date-parts":[[2019,11,1]],"date-time":"2019-11-01T04:18:15Z","timestamp":1572581895000},"page":"164-176","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["A bioengineered living cell construct activates metallothionein\/zinc\/MMP8 and inhibits TGF<b>\u03b2<\/b> to stimulate remodeling of fibrotic venous leg ulcers"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7489-2123","authenticated-orcid":false,"given":"Rivka C.","family":"Stone","sequence":"first","affiliation":[{"name":"Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami\u2010Miller School of Medicine  Miami Florida"},{"name":"The Research Residency Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami\u2010Miller School of Medicine  Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivera","family":"Stojadinovic","sequence":"additional","affiliation":[{"name":"Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami\u2010Miller School of Medicine  Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Sawaya","sequence":"additional","affiliation":[{"name":"Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami\u2010Miller School of Medicine  Miami Florida"},{"name":"Molecular and Cellular Pharmacology Graduate Program in Biomedical Sciences University of Miami\u2010Miller School of Medicine  Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George D.","family":"Glinos","sequence":"additional","affiliation":[{"name":"Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami\u2010Miller School of Medicine  Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linsey E.","family":"Lindley","sequence":"additional","affiliation":[{"name":"Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami\u2010Miller School of Medicine  Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0197-6198","authenticated-orcid":false,"given":"Irena","family":"Pastar","sequence":"additional","affiliation":[{"name":"Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami\u2010Miller School of Medicine  Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelos","family":"Badiavas","sequence":"additional","affiliation":[{"name":"Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami\u2010Miller School of Medicine  Miami Florida"},{"name":"Interdisciplinary Stem Cell Institute University of Miami\u2010Miller School of Medicine  Miami Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9341-0193","authenticated-orcid":false,"given":"Marjana","family":"Tomic\u2010Canic","sequence":"additional","affiliation":[{"name":"Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami\u2010Miller School of Medicine  Miami Florida"},{"name":"John P. 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