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Transcriptomic, Proteomic, and Functional Long-Term Characterization of Multicellular Three-Dimensional Human Liver
Simon Messner1, Lisa Fredriksson2, Volker M Lauschke2
1InSphero AG, Schlieren, Switzerland.
Applied in Vitro Toxicology
|September 21, 2020
Summary
This study characterizes 3D human liver microtissues (hLiMTs) for long-term toxicology. These microtissues maintain stable liver function and gene expression for 5 weeks, proving suitable for repeated-dose toxicity testing.
Area of Science:
- * In vitro toxicology and drug development
- * Liver biology and regenerative medicine
- * Omics technologies in biomedical research
Background:
- * Three-Dimensional (3D) liver microtissues from primary human hepatocytes (PHH) and nonparenchymal cells (NPCs) are valuable for in vitro toxicology.
- * Limited long-term characterization data exists for these models at functional, transcriptomic, and proteomic levels.
- * Need for physiologically relevant in vitro models for accurate toxicity assessment.
Purpose of the Study:
- * To conduct an in-depth, long-term characterization of 3D human liver microtissues (hLiMTs).
- * To assess the functional, transcriptomic, and proteomic stability of hLiMTs over 5 weeks of cultivation.
- * To evaluate the suitability of hLiMTs for repeated-dose toxicity testing.
Main Methods:
- * Coculture of primary human hepatocytes (PHH) with primary nonparenchymal cells (NPCs) to form 3D liver microtissues.
- * Integration of multiple omics technologies: RNA arrays and label-free LC-MS/MS proteomics.
- * Functional assays including adenosine triphosphate (ATP) content, albumin secretion, and cytochrome P450 activity measurements.
- * Histological analysis of tissue structure and protein localization (BSEP, MRP2).
Main Results:
- * Stable adenosine triphosphate (ATP) content and albumin secretion observed over 5 weeks.
- * Histology revealed healthy tissue with polarized expression of BSEP and MRP2, mimicking bile canaliculi.
- * Stable basal and inducible cytochrome P450 activities were maintained up to 5 weeks.
- * Transcriptomic analysis showed similarities to native human liver gene expression, with stable phenotype over time.
- * Proteomic profiling indicated relatively stable protein expression, with minimal significant changes (<7.3%) from day 7 to 35.
- * Donor variability was identified as the primary driver of differences in liver gene expression.
Conclusions:
- * 3D human liver microtissues (hLiMTs) represent a responsive and physiologically relevant in vitro liver model.
- * hLiMTs maintain stable liver function and phenotype for up to 5 weeks in culture.
- * These microtissues are well-suited for repeated-dose toxicity testing, offering a valuable tool for drug development and toxicology studies.
