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

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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.

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Abbreviations

HSC:

Hepatic stellate cells

ECM:

Extracellular matrix

Fn:

Fibronectin

BMP:

Bone morphogenetic protein

RCAS:

Vector of replication-competent ALV LTR with a splice acceptor

E:

Embryonic day

LCAM:

Liver cell adhesion molecule

Flk-1:

Fetal liver kinase-1

α-SMA:

Alpha-smooth muscle actin

p75NTR:

p75 Neurotrophin receptor

MMP:

Matrix metalloproteinase

PCNA:

Proliferative cell nuclear antigen

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Pathology, University of Southern California, HMR 315B, 2011 Zonal Ave., Los Angeles, CA, 90033, USA

    Ming-Shian Tsai, Sanong Suksaweang, Ting-Xin Jiang, Ping Wu, Randall Widelitz & Cheng-Ming Chuong

  2. School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan

    Ming-Shian Tsai, Ying-Hsien Kao & Po-Huang Lee

  3. Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan

    Ming-Shian Tsai, Ying-Hsien Kao & Po-Huang Lee

  4. Department of Pathology and Laboratory Medicine, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima, 30000, Thailand

    Sanong Suksaweang

  5. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan

    Po-Huang Lee

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  1. Ming-Shian Tsai
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  2. Sanong Suksaweang
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Correspondence to Cheng-Ming Chuong.

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Tsai, MS., Suksaweang, S., Jiang, TX. et al. Proper BMP Signaling Levels Are Essential for 3D Assembly of Hepatic Cords from Hepatoblasts and Mesenchymal Cells. Dig Dis Sci 60, 3669–3680 (2015). https://doi.org/10.1007/s10620-015-3798-2

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  • DOI: https://doi.org/10.1007/s10620-015-3798-2

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