Proper BMP Signaling Levels Are Essential for 3D Assembly of Hepatic Cords from Hepatoblasts and Mesenchymal Cells
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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.
KeywordsEpithelial morphogenesis Epithelial–mesenchymal interaction Tissue engineering Liver stem cells Fibronectin Regeneration
Hepatic stellate cells
Bone morphogenetic protein
Vector of replication-competent ALV LTR with a splice acceptor
Liver cell adhesion molecule
Fetal liver kinase-1
Alpha-smooth muscle actin
p75 Neurotrophin receptor
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.
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