Ming-Shian Tsai1,2,3, Sanong Suksaweang1,4, Ting-Xin Jiang1, Ping Wu1, Ying-Hsien Kao2,3, Po-Huang Lee2,3,5, Randall Widelitz1, Cheng-Ming Chuong6. 1. Department of Pathology, University of Southern California, HMR 315B, 2011 Zonal Ave., Los Angeles, CA, 90033, USA. 2. School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan. 3. Department of Surgery, E-Da Hospital, Kaohsiung, Taiwan. 4. Department of Pathology and Laboratory Medicine, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima, 30000, Thailand. 5. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan. 6. Department of Pathology, University of Southern California, HMR 315B, 2011 Zonal Ave., Los Angeles, CA, 90033, USA. cmchuong@usc.edu.
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.
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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