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The use of proinflammatory cytokines as stimuli to improve the reparative efficacy of mesenchymal stem cells (MSCs) towards damaged tissues represents an evolving field of investigation. However, the therapeutic benefits of this strategy in the treatment of urethral stricture remain unknown. Here, we enriched exosomes derived from human umbilical cord\u2010derived MSCs pretreated with or without tumor necrosis factor alpha (TNF\u2010\u03b1) to evaluate their therapeutic effects in an in vivo model of TGF\u03b21\u2010induced urethral stricture. Male Sprague\u2010Dawley rats received sham (saline) or TGF\u03b21 injections to urethral tissues followed by incisions in the urethra. Animals in the TGF\u03b21 injection (urethral fibrosis) cohort were subsequently injected with vehicle control, or with exosomes derived from MSCs cultured with or without TNF\u2010\u03b1. After 4 weeks, rats underwent ultrasound evaluation and, following euthanasia, urethral tissues were harvested for histological and molecular analysis. In vitro, the effects of MSC\u2010derived exosomes on fibroblast secretion of collagen and cytokines were studied by enzyme\u2010linked immunosorbent assay (ELISA), quantitative real\u2010time polymerase chain reaction (qRT\u2010PCR), and western blot analysis. Exosomes derived from MSCs pretreated with TNF\u2010\u03b1 were more effective in suppressing urethral fibrosis and stricture than exosomes from untreated MSCs. We found that miR\u2010146a, an anti\u2010inflammatory miRNA, was strongly upregulated in TNF\u2010\u03b1\u2010stimulated MSCs and was selectively packaged into exosomes. Moreover, miR\u2010146a\u2010containing exosomes were taken up by fibroblasts and inhibited fibroblast activation and associated inflammatory responses, a finding that may underlie the therapeutic mechanism for suppression of urethral stricture. Inhibition of miR\u2010146a in TNF\u2010\u03b1\u2010treated MSCs partially reduced antifibrotic effects and increased the release of proinflammatory factors of exosomes derived from these cells. Together these findings demonstrate that exosomes derived from TNF\u2010\u03b1\u2010treated MSCs are of therapeutic benefit in urethral fibrosis, suggesting that this strategy may have utility as an adjuvant therapy in the treatment of urethral stricture diseases.<\/jats:p>","DOI":"10.1002\/jcp.28891","type":"journal-article","created":{"date-parts":[[2019,5,30]],"date-time":"2019-05-30T04:00:39Z","timestamp":1559188839000},"page":"23243-23255","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["TNF\u2010\u03b1\u2010induced exosomal miR\u2010146a mediates mesenchymal stem cell\u2010dependent suppression of urethral stricture"],"prefix":"10.1002","volume":"234","author":[{"given":"Ying\u2010Chun","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Urology The First Affiliated Hospital of Fujian Medical University Fuzhou 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