Developing scalable cultivation systems of hepatic spheroids for drug metabolism via genomic and functional analyses = 게놈 및 기능 분석을 통한 약물 대사용 확장 가능한 간 회전 타원체 배양 시스템 개발

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Title
Developing scalable cultivation systems of hepatic spheroids for drug metabolism via genomic and functional analyses = 게놈 및 기능 분석을 통한 약물 대사용 확장 가능한 간 회전 타원체 배양 시스템 개발
Author(s)
Jiwon Ahn; Ho-Joon Lee; S J Oh; Wantae Kim; Seon Ju Mun; Jae Hye Lee; Cho Rok JungHyun Soo ChoDae Soo KimMyung Jin SonKyung-Sook Chung
Bibliographic Citation
Biotechnology and Bioengineering, vol. 116, pp. 1496-1508
Publication Year
2019
Abstract
Spheroids, a widely used three-dimensional (3D) culture model, are standard in hepatocyte culture as they preserve long-term hepatocyte functionality and enhance survivability. In this study, we investigated the effects of three operation modes in 3D culture ? static, orbital shaking, and under vertical bidirectional flow using spheroid forming units (SFUs) on hepatic differentiation and drug metabolism to propose the best for mass production of functionally enhanced spheroids. Spheroids in SFUs exhibited increased hepatic gene expression, albumin secretion, and cytochrome P450 3A4 (CYP3A4) activity during the differentiation period (12 days). SFUs advantages include facilitated mass production and a relatively earlier peak of CYP3A4 activity. However, CYP3A4 activity was not well maintained under dimethyl sulfoxide (DMSO)-free conditions (13?18 days), dramatically reducing drug metabolism capability. Continued shear stimulation without differentiation stimuli in assay conditions markedly attenuated CYP3A4 activity, which was less severe in static conditions. In this condition, SFU spheroids exhibited dedifferentiation characteristics, such as increased proliferation and Notch signaling genes. We found that the dedifferentiation could be overcome by using the serum-free medium formulation. Therefore, we suggest that SFUs represent the best option for the mass production of functionally improved spheroids and so the serum-free conditions should be maintained during drug metabolism analysis.
Keyword
hepatocyteserumfreeshearspheroid forming unitthreedimensional culture
ISSN
0006-3592
Publisher
Wiley
DOI
http://dx.doi.org/10.1002/bit.26954
Type
Article
Appears in Collections:
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
Division of Research on National Challenges > Environmental diseases research center > 1. Journal Articles
Division of Research on National Challenges > 1. Journal Articles
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