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Drug cytotoxicity screening using human intestinal organoids propagated with extensive cost-reduction strategies.

ABSTRACT: Organoids are regarded as physiologically relevant cell models and useful for compound screening for drug development; however, their applications are currently limited because of the high cost of their culture. We previously succeeded in reducing the cost of human intestinal organoid culture using conditioned medium (CM) of L cells co-expressing Wnt3a, R-spondin1, and Noggin. Here, we further reduced the cost by replacing recombinant hepatocyte growth factor with CM. Moreover, we showed that embedding organoids in collagen gel, a more inexpensive matrix than Matrigel, maintains organoid proliferation and marker gene expression similarly when using Matrigel. The combination of these replacements also enabled the organoid-oriented monolayer cell culture. Furthermore, screening thousands of compounds using organoids expanded with the refined method identified several compounds with more selective cytotoxicity against organoid-derived cells than Caco-2 cells. The mechanism of action of one of these compounds, YC-1, was further elucidated. We showed that YC-1 induces apoptosis through the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway, the mechanism of which was distinct from cell death caused by other hit compounds. Our cost-cutting methodology enables large-scale intestinal organoid culture and subsequent compound screening, which could expand the application of intestinal organoids in various research fields.

SUBMITTER: Takahashi Y

PROVIDER: S-EPMC10070462 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Drug cytotoxicity screening using human intestinal organoids propagated with extensive cost-reduction strategies.

Takahashi Yu Y Inoue Yu Y Sato Shintaro S Okabe Takayoshi T Kojima Hirotatsu H Kiyono Hiroshi H Shimizu Makoto M Yamauchi Yoshio Y Sato Ryuichiro R

Scientific reports 20230403 1

Organoids are regarded as physiologically relevant cell models and useful for compound screening for drug development; however, their applications are currently limited because of the high cost of their culture. We previously succeeded in reducing the cost of human intestinal organoid culture using conditioned medium (CM) of L cells co-expressing Wnt3a, R-spondin1, and Noggin. Here, we further reduced the cost by replacing recombinant hepatocyte growth factor with CM. Moreover, we showed that em ...[more]

PMID: 37012293

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Project description:Osteoporosis affects many men, with significant morbidity and mortality. However, the best osteoporosis screening strategies for men are unknown. We developed an individual-level state-transition cost-effectiveness model with a lifetime time horizon to identify the cost-effectiveness of different osteoporosis screening strategies for US men involving various screening tests (dual-energy X-ray absorptiometry [DXA]; the Osteoporosis Self-Assessment Tool [OST]; or a fracture risk assessment strategy using age, femoral neck bone mineral density [BMD], and Vertebral Fracture Assessment [VFA]); screening initiation ages (50, 60, 70, or 80 years); and repeat screening intervals (5 years or 10 years). In base-case analysis, no screening was a less effective option than all other strategies evaluated; furthermore, no screening was more expensive than all strategies that involved screening with DXA or the OST risk assessment instrument, and thus no screening was "dominated" by screening with DXA or OST at all evaluated screening initiation ages and repeat screening intervals. Screening strategies that most frequently appeared as most cost-effective in base-case analyses and one-way sensitivity analyses when assuming willingness-to-pay of $50,000/quality-adjusted life-year (QALY) or $100,000/QALY included screening initiation at age 50 years with the fracture risk assessment strategy and repeat screening every 10 years; screening initiation at age 50 years with fracture risk assessment and repeat screening every 5 years; and screening initiation at age 50 years with DXA and repeat screening every 5 years. In conclusion, expansion of osteoporosis screening for US men to initiate routine screening at age 50 or 60 years would be expected to be effective and of good value for improving health outcomes. A fracture risk assessment strategy using variables of age, femoral neck BMD, and VFA is likely to be the most effective of the evaluated strategies within accepted cost-effectiveness parameters. DXA and OST are also reasonable screening options, albeit likely slightly less effective than the evaluated fracture risk assessment strategy. © 2016 American Society for Bone and Mineral Research.

Dataset Information

Drug cytotoxicity screening using human intestinal organoids propagated with extensive cost-reduction strategies.

Publications

Drug cytotoxicity screening using human intestinal organoids propagated with extensive cost-reduction strategies.

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