Digestive Diseases and Sciences

, Volume 60, Issue 12, pp 3669–3680 | Cite as

Proper BMP Signaling Levels Are Essential for 3D Assembly of Hepatic Cords from Hepatoblasts and Mesenchymal Cells

  • Ming-Shian Tsai
  • Sanong Suksaweang
  • Ting-Xin Jiang
  • Ping Wu
  • Ying-Hsien Kao
  • Po-Huang Lee
  • Randall Widelitz
  • Cheng-Ming Chuong
Original Article



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.


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.


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.


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.


Epithelial morphogenesis Epithelial–mesenchymal interaction Tissue engineering Liver stem cells Fibronectin Regeneration 



Hepatic stellate cells


Extracellular matrix




Bone morphogenetic protein


Vector of replication-competent ALV LTR with a splice acceptor


Embryonic day


Liver cell adhesion molecule


Fetal liver kinase-1


Alpha-smooth muscle actin


p75 Neurotrophin receptor


Matrix metalloproteinase


Proliferative cell nuclear antigen



This work was supported by NIH grants to CMC (NIAMS AR 47364, and AR 60306). MST was funded by a Research Fellowship Grant from E-Da hospital, Kaohsiung, Taiwan (EDAHP-10004). SS was supported by a Royal Thai Government Scholarship from Thailand when he was at USC. The work was also supported by the USC Research Center for Liver Diseases, NIH grants 5P30DK048522-06 and 5P30DK048522-07 (PI: Dr Neil Kaplowitz). We acknowledge Drs Neil Kaplowitz, Hide Tsukamato, and James Ou for discussion. We thank Michele McVeigh and the Microscopy Sub Core at the USC Center for Liver Diseases (NIH 1 P03 DK48522) for help with confocal microscopy.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10620_2015_3798_MOESM1_ESM.doc (7.9 mb)
Supplementary material 1 (DOC 8053 kb)
10620_2015_3798_MOESM2_ESM.avi (25.3 mb)
Supplementary material 2 (AVI 25920 kb)


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Ming-Shian Tsai
    • 1
    • 2
    • 3
  • Sanong Suksaweang
    • 1
    • 4
  • Ting-Xin Jiang
    • 1
  • Ping Wu
    • 1
  • Ying-Hsien Kao
    • 2
    • 3
  • Po-Huang Lee
    • 2
    • 3
    • 5
  • Randall Widelitz
    • 1
  • Cheng-Ming Chuong
    • 1
  1. 1.Department of PathologyUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.School of Chinese Medicine for Post-BaccalaureateI-Shou UniversityKaohsiungTaiwan
  3. 3.Department of SurgeryE-Da HospitalKaohsiungTaiwan
  4. 4.Department of Pathology and Laboratory Medicine, Institute of MedicineSuranaree University of TechnologyNakhon RatchasimaThailand
  5. 5.Department of SurgeryNational Taiwan University HospitalTaipeiTaiwan

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