title: In vivo hepatogenic capacity and therapeutic potential of stem cells from human exfoliated deciduous teeth in liver fibrosis in mice.
abstract: BACKGROUND
  Liver transplantation is a gold standard treatment for intractable liver diseases. Because of the shortage of donor organs, alternative therapies have been required. Due to their potential to differentiate into a variety of mature cells, stem cells are considered feasible cell sources for liver regeneration. Stem cells from human exfoliated deciduous teeth (SHED) exhibit hepatogenic capability in vitro. In this study, we investigated their in vivo capabilities of homing and hepatocyte differentiation and therapeutic efficacy for liver disorders in carbon tetrachloride (CCl4)-induced liver fibrosis model mice.
  
  
  METHODS
  We transplanted SHED into CCl4-induced liver fibrosis model mice through the spleen, and analyzed the in vivo homing and therapeutic effects by optical, biochemical, histological, immunological and molecular biological assays. We then sorted human leukocyte antigen-ABC (HLA-ABC)-positive cells from primary CCl4-damaged recipient livers, and analyzed their fusogenicity and hepatic characteristics by flow cytometric, genomic DNA, hepatocyte-specific gene assays. Furthermore, we examined the treatment effects of HLA-positive cells to a hepatic dysfunction by a secondary transplantation into CCl4-treated mice.
  
  
  RESULTS
  Transplanted SHED homed to recipient livers, and expressed HLA-ABC, human hepatocyte specific antigen hepatocyte paraffin 1 and human albumin. SHED transplantation markedly recovered liver dysfunction and led to anti-fibrotic and anti-inflammatory effects in the recipient livers. SHED-derived HLA-ABC-positive cells that were sorted from the primary recipient liver tissues with CCl4 damage did not fuse with the host mouse liver cells. Sorted HLA-positive cells not only expressed human hepatocyte-specific genes including albumin, cytochrome P450 1A1, fumarylacetoacetase, tyrosine aminotransferase, uridine 5'-diphospho-glucuronosyltransferase, transferrin and transthyretin, but also secreted human albumin, urea and blood urea nitrogen. Furthermore, SHED-derived HLA-ABC-positive cells were secondary transplanted into CCl4-treated mice. The donor cells homed into secondary recipient livers, and expressed hepatocyte paraffin 1 and human albumin, as well as HLA-ABC. The secondary transplantation recovered a liver dysfunction in secondary recipients.
  
  
  CONCLUSIONS
  This study indicates that transplanted SHED improve hepatic dysfunction and directly transform into hepatocytes without cell fusion in CCl4-treated mice, suggesting that SHED may provide a feasible cell source for liver regeneration.
authors.affiliation: Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. yamazata@dent.kyushu-u.ac.jp.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Yamaza
authors.affiliation: Department of Pediatric Surgery, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. safiraalatas@gmail.com.
authors.forename: Fatima Safira
authors.initials: FS
authors.lastname: Alatas
authors.affiliation: Department of Pediatric Surgery, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. artha00@gmail.com.
authors.forename: Ratih
authors.initials: R
authors.lastname: Yuniartha
authors.affiliation: Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. hyamaza@dent.kyushu-u.ac.jp.
authors.forename: Haruyoshi
authors.initials: H
authors.lastname: Yamaza
authors.affiliation: Department of Pediatrics, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. jjkk0323@pediatr.med.kyushu-u.ac.jp.
authors.forename: Junko K
authors.initials: JK
authors.lastname: Fujiyoshi
authors.affiliation: Department of Pediatric Surgery, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. y-yanag@pedsurg.med.kyushu-u.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yanagi
authors.affiliation: Department of Pediatric Surgery, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. yosimaru@pedsurg.med.kyushu-u.ac.jp.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Yoshimaru
authors.affiliation: Department of Pediatric Surgery, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. makoto-h@pedsurg.med.kyushu-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hayashida
authors.affiliation: Department of Pediatric Surgery, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. matsuura@pedsurg.med.kyushu-u.ac.jp.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Matsuura
authors.affiliation: Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. leona@dent.kyushu-u.ac.jp.
authors.forename: Reona
authors.initials: R
authors.lastname: Aijima
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hazama-cho, Yuhuin, 879-5593, Japan. k-ihara@oita-u.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ihara
authors.affiliation: Department of Pediatrics, Faculty of Medicine and Health Sciences, Yamaguchi University, 1-1-1 Minami Ogushi, Ube, 755-8505, Japan. ohgas@yamaguchi-u.ac.jp.
authors.forename: Shouichi
authors.initials: S
authors.lastname: Ohga
authors.affiliation: Department Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Philadelphia, PA, 19104-6030, USA. songtaos@dental.upenn.edu.
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. nonaka@dent.kyushu-u.ac.jp.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nonaka
authors.affiliation: Department of Pediatric Surgery, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. taguchi@pedsurg.med.kyushu-u.ac.jp.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Taguchi
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002648:Child; D003782:Dental Pulp / Q000166:cytology; D006680:HLA Antigens / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice
chemical_list: D015415:Biomarkers; D006680:HLA Antigens