title: Proper BMP Signaling Levels Are Essential for 3D Assembly of Hepatic Cords from Hepatoblasts and Mesenchymal Cells.
abstract: BACKGROUND
  Because the molecular mechanisms of morphogenesis of the hepatic cord and sinus are unclear, we investigated the involvement of bone morphogenetic protein (BMP4) in hepatic sinusoid morphogenesis.
  
  
  METHODS
  We used embryonic chicken livers, which develop rapidly, as our model, and investigated expression of BMP-related genes. BMP4 activity was manipulated by overexpressing BMP4 and its antagonist, noggin.
  
  
  RESULTS
  During hepatic cord morphogenesis, BMP4 and its receptors are expressed in both peri-sinusoidal cells and hepatoblasts as the sinusoids form, whereas noggin is expressed transiently in peri-sinusoidal cells at early stages. Suppression of BMP activity with noggin overexpression disrupted normal hepatic sinusoid structure, leading to liver congestion, failure of fibronectin deposition, and markedly reduced numbers of peri-sinusoidal cells. However, overexpression of BMP did not change sinusoidal morphology but increased endothelial cell number. Noggin overexpression resulted in disrupted cord organization, and dilated sinusoidal space, eventually leading to increased apoptosis and failed hepatocyte differentiation.
  
  
  CONCLUSIONS
  Our results show that proper BMP signaling mediates peri-sinusoidal cell-hepatoblast interactions during development; this is essential for hepatic cord organization among hepatoblasts, endothelium, and presumptive hepatic stellate cells.
authors.affiliation: Department of Pathology, University of Southern California, HMR 315B, 2011 Zonal Ave., Los Angeles, CA, 90033, USA.|School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan.|Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan.
authors.forename: Ming-Shian
authors.initials: MS
authors.lastname: Tsai
authors.affiliation: Department of Pathology, University of Southern California, HMR 315B, 2011 Zonal Ave., Los Angeles, CA, 90033, USA.|Department of Pathology and Laboratory Medicine, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima, 30000, Thailand.
authors.forename: Sanong
authors.initials: S
authors.lastname: Suksaweang
authors.affiliation: Department of Pathology, University of Southern California, HMR 315B, 2011 Zonal Ave., Los Angeles, CA, 90033, USA.
authors.forename: Ting-Xin
authors.initials: TX
authors.lastname: Jiang
authors.affiliation: Department of Pathology, University of Southern California, HMR 315B, 2011 Zonal Ave., Los Angeles, CA, 90033, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan.|Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan.
authors.forename: Ying-Hsien
authors.initials: YH
authors.lastname: Kao
authors.affiliation: School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan.|Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan.|Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
authors.affiliation: Department of Pathology, University of Southern California, HMR 315B, 2011 Zonal Ave., Los Angeles, CA, 90033, USA.
authors.forename: Randall
authors.initials: R
authors.lastname: Widelitz
authors.affiliation: Department of Pathology, University of Southern California, HMR 315B, 2011 Zonal Ave., Los Angeles, CA, 90033, USA. cmchuong@usc.edu.
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chuong
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication; D002642:Chick Embryo; D018507:Gene Expression Regulation, Developmental; D055166:Hepatic Stellate Cells / Q000502:physiology*; D008099:Liver / Q000196:embryology* / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D015398:Signal Transduction; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D000099176:Noggin Protein
keywords: Epithelial morphogenesis; Epithelial–mesenchymal interaction; Fibronectin; Liver stem cells; Regeneration; Tissue engineering