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The aim of this study was to investigate the action of melatonin on hepatic differentiation as well as its related signaling pathways of human dental pulp stem cells (hDPSC<\/jats:styled-content>s) and to examine the therapeutic effects of a combination of melatonin and hDPSC<\/jats:styled-content> transplantation on carbon tetrachloride (CC<\/jats:styled-content>l4<\/jats:sub>)\u2010induced liver fibrosis in mice. In vitro hepatic differentiation was assessed by periodic acid\u2010Schiff (PAS<\/jats:styled-content>) staining and mRNA<\/jats:styled-content> expression for hepatocyte markers. Liver fibrosis model was established by injecting 0.5\u00a0mL\/kg CC<\/jats:styled-content>l4<\/jats:sub> followed by treatment with melatonin (5\u00a0mg\/kg, twice a week) and hDPSC<\/jats:styled-content>s. In vivo therapeutic effects were evaluated by histopathology and by means of liver function tests including measurement of alanine transaminase (ALT<\/jats:styled-content>), aspartate transaminase (AST<\/jats:styled-content>), and ammonia levels. Melatonin promoted hepatic differentiation based on mRNA<\/jats:styled-content> expression of differentiation markers and PAS<\/jats:styled-content>\u2010stained glycogen\u2010laden cells. In addition, melatonin increased bone morphogenic protein (BMP<\/jats:styled-content>)\u20102 expression and Smad1\/5\/8 phosphorylation, which was blocked by the BMP<\/jats:styled-content> antagonist noggin. Furthermore, melatonin activated p38, extracellular signal\u2010regulated kinase (ERK<\/jats:styled-content>), and nuclear factor\u2010\u03ba<\/jats:italic>B (NF<\/jats:styled-content>\u2010\u03ba<\/jats:italic>B) in hDPSC<\/jats:styled-content>s. Melatonin\u2010induced hepatic differentiation was attenuated by inhibitors of BMP<\/jats:styled-content>, p38, ERK<\/jats:styled-content>, and NF<\/jats:styled-content>\u2010\u03ba<\/jats:italic>B. Compared to treatment of CC<\/jats:styled-content>l4<\/jats:sub>\u2010injured mice with either melatonin or hDPSC<\/jats:styled-content> transplantation alone, the combination of melatonin and hDPSC<\/jats:styled-content> significantly suppressed liver fibrosis and restored ALT<\/jats:styled-content>, AST<\/jats:styled-content>, and ammonia levels. For the first time, this study demonstrates that melatonin promotes hepatic differentiation of hDPSC<\/jats:styled-content>s by modulating the BMP<\/jats:styled-content>, p38, ERK<\/jats:styled-content>, and NF<\/jats:styled-content>\u2010\u03ba<\/jats:italic>B pathway. Combined treatment of grafted hDPSC<\/jats:styled-content>s and melatonin could be a viable approach for the treatment of liver cirrhosis.<\/jats:p>","DOI":"10.1111\/jpi.12198","type":"journal-article","created":{"date-parts":[[2014,11,28]],"date-time":"2014-11-28T09:12:01Z","timestamp":1417165921000},"page":"127-135","source":"Crossref","is-referenced-by-count":68,"title":["Melatonin promotes hepatic differentiation of human dental pulp stem cells: clinical implications for the prevention of liver fibrosis"],"prefix":"10.1111","volume":"58","author":[{"given":"Young\u2010Ah","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial Pathology School of Dentistry and Research Center for Tooth & Periodontal Regeneration (MRC) Kyung Hee University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwantae","family":"Noh","sequence":"additional","affiliation":[{"name":"Department of Prosthodontics School of Dentistry Kyung Hee 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