Construction of region-specific liver organoid and fabrication of hierarchical functional liver lobule for liver disease modeling and drug evaluation
Peer-Reviewed Publication
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The study of liver disease models, drug screening, and toxicity assessment has been hindered by the lack of faithful representations of liver models. This work unveiled key signaling pathways in liver zonation and constructed genetically modified liver sinusoidal endothelial cells. It was found that SK-Hep1 cells overexpressing WNT2 and DLL4 promote zonated functional differentiation of primary hepatic organoids. Further investigation revealed that genetically modified SK-Hep1 cells regulate hepatocyte functional differentiation through ligand-receptor interactions. Moreover, this modification enhanced the sensitivity of hepatocytes to hepatotoxic drugs and simulated drug-induced injury repair and regeneration processes in hepatic organoids. A co-culture system of liver organoids and genetically modified SK-Hep1 cells was established for liver disease modeling and drug screening. Finally, we successfully employed 3D bioprinting technology to fabricate liver lobule models with specific morphological and functional architectures. These models effectively demonstrated region-specific hepatic injuries induced by pharmaceutical agents. These findings provide new insights into the understanding of liver functional differentiation and offer valuable references for liver disease treatment and drug screening research.
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