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Int J Mol Med. 2019 Nov;44(5):1653-1666. doi: 10.3892/ijmm.2019.4321. Epub 2019 Aug 21.

A simplified 3D liver microsphere tissue culture model for hepatic cell signaling and drug-induced hepatotoxicity studies.

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Ministry of Education Key Laboratory of Diagnostic Medicine, School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China.
Department of Biostatistics, School of Public Health and Management, Chongqing Medical University, Chongqing 400016, P.R. China.
Key Laboratory of Molecular Biology for Infectious Diseases of The Ministry of Education of China, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400037, P.R. China.
Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA.


Although a number of experimental models have been developed for liver research, each has its own advantages and disadvantages. The present study attempted to develop a simple and effective 3‑dimensional mouse liver microsphere tissue culture (LMTC) model in vitro for the analysis of hepatic functions. Hepatic characteristics and potential applications of this model were compared with that of mouse model in vivo and mouse primary hepatocytes in vitro. Using freshly‑perfused mouse liver tissue passed through 80‑mesh sift strainer (sift80), it was demonstrated that under the optimal culture conditions, the sift80 microsphere tissue cultured in 2% bovine calf serum medium remained viable with marked proliferating cell nuclear antigen and anti‑Myc proto‑oncogene protein expression, exhibited normal hepatic functions including indocyanine green (ICG) uptake/release and periodic acid‑Schiff staining, and expressed hepatocyte‑specific genes for up to 2 weeks. The microsphere tissue was responsive to bone morphogenic protein 9 (BMP9) stimulation leading to upregulation of downstream targets of BMP9 signaling. Furthermore, 3 commonly‑used liver‑damaging drugs were indicated to effectively inhibit hepatic ICG uptake, and induce the expression of hepatotoxicity‑associated genes. Therefore, this simplified LMTC model may be a useful in vitro tissue culture model to investigate drug‑induced liver injury and metabolism, and hepatocyte‑based cell singling.

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