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| Status |
Public on Apr 21, 2021 |
| Title |
Patient derived colonoids as drug testing platforms - critical importance of oxygen concentration |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Treatment of inflammatory bowel disease (IBD) is challenging, with a series of available drugs each helping only a fraction of patients. Patients may face time-consuming drug trials while the disease is active, thus there is an unmet need for biomarkers and assays to predict drug effect. It is well known that the intestinal epithelium is an important factor in disease pathogenesis, exhibiting physical, biochemical and immunologic driven barrier dysfunctions. One promising test system to study effects of existing or emerging IBD treatments targeting intestinal epithelial cells (IECs) is intestinal organoids (“mini-guts”). However, the fact that healthy intestinal epithelium is in a physiologically hypoxic state has largely been neglected, and studies with intestinal organoids are mainly performed at oxygen concentration of 20%. We hypothesized that lowering the incubator oxygen level from 20% to 2% would recapitulate better the in vivo physiological environment of colonic epithelial cells and enhance the translational value of intestinal organoids as a drug testing platform. In the present study we examine the effects of the key IBD cytokines and drug targets TNF/IL17 on human colonic organoids (colonoids) under atmospheric (20%) or reduced (2%) O2. We show that colonoids derived from both healthy controls and IBD-patients are viable and responsive to IBD-relevant cytokines at 2% oxygen. Because chemokine release is one of the important immunoregulatory traits of the epithelium that may be fine-tuned by IBD-drugs, we also examined chemokine expression and release at different oxygen concentrations. We show that chemokine responses to TNF/IL17 in organoids display similarities to inflamed epithelium in IBD-patients. However, inflammation-associated genes induced by TNF/IL17 were attenuated at low oxygen concentration. We detected substantial oxygen-dependent differences in gene expression in untreated as well as TNF/IL17 treated colonoids in all donors. Further, for some of the IBD-relevant cytokines differences between colonoids from healthy controls and IBD patients were more pronounced in 2% O2 than 20% O2. Our results strongly indicate that an oxygen concentration similar to the in vivo epithelial cell environment is of essence in experimental pharmacology.
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| Overall design |
Gene expression data of differentiated colon organoids from 6 donors (3 Ulcerative colitis and 3 healthy controls) investigating effects of short-term hypoxia on drug-treatment targets such as TNF alone or in combination with IL17.
***Please note that raw data is not provided as Norwegian law does not allow public access to human sequences raw data***
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| Contributor(s) |
Skovdahl HK, Gopalakrishnan S, Svendsen TD, van Beelen Granlund A, Bakke I, Flatberg A, Ginbot ZG, Thorsvik S, Ostrop J, Sporsheim B, Mollnes TE, Sandvik AK, Bruland T |
| Citation(s) |
34054553, 35655783, 36911731 |
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| Submission date |
Apr 20, 2021 |
| Last update date |
Jun 23, 2023 |
| Contact name |
Atle van Beelen Granlund |
| E-mail(s) |
atlegran@ntnu.no
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| Organization name |
Norwegian University of Science and Technology
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| Street address |
Postboks 8905 MTFS
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| City |
Trondheim |
| ZIP/Postal code |
7491 |
| Country |
Norway |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (36)
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| Relations |
| BioProject |
PRJNA723260 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE172404_RAW.tar |
76.2 Mb |
(http)(custom) |
TAR (of SF) |
| Raw data not provided for this record |
| Processed data provided as supplementary file |
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