Phenotypic landscape of intestinal organoid regeneration
Open accessAbstract
The development of intestinal organoids from single adult intestinal stem cells in vitro recapitulates the regenerative capacity of the intestinal epithelium 1,2. Here we unravel the mechanisms that orchestrate both organoid formation and the regeneration of intestinal tissue, using an image-based screen to assay an annotated library of compounds. We generate multivariate feature profiles for hundreds of thousands of organoids to quantitatively describe their phenotypic landscape. We then use these phenotypic fingerprints to infer regulatory genetic interactions, establishing a new approach to the mapping of genetic interactions in an emergent system. This allows us to identify genes that regulate cell-fate transitions and maintain the balance between regeneration and homeostasis, unravelling previously unknown roles for several pathways, among them retinoic acid signalling. We then characterize a crucial role for retinoic acid nuclear receptors in controlling exit from the regenerative state and driving enterocyte differentiation. By combining quantitative imaging with RNA sequencing, we show the role of endogenous retinoic acid metabolism in initiating transcriptional programs that guide the cell-fate transitions of intestinal epithelium, and we identify an inhibitor of the retinoid X receptor that improves intestinal regeneration in vivo.
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Several examples have documented the power of chemical screens in organoids or directly in patient material.
“To that end, several examples have documented the power of chemical screens in organoids175,176 or directly in patient material.177−179”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [175]
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- Authors
- Lukonin, I., Serra, D., Challet Meylan, L., Volkmann, K., Baaten, J., Zhao, R., Meeusen, S., Colman, K., Maurer, F., Stadler, M. B., Jenkins, J., & Liberali, P.
- Affiliations
- University of Basel (CH)
- Friedrich Miescher Institute (CH)
- Genomics Institute of the Novartis Research Foundation (US)
- SIB Swiss Institute of Bioinformatics (CH)
- Corresponding author
- Liberali, Prisca
- Venue
- Nature
- Published
- 2020-10-07
- Volume
- 586
- Issue
- 7828
- Pages
- 275-280
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7116869
- OpenAlex
- W3092537844
- Cited by
- 283
- References
- 47
- Citations by year
- 2026: 38 · 2025: 42 · 2024: 37 · 2023: 56 · 2022: 56 · 2021: 44 · 2020: 9
- FWCI
- 24.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (157531)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- intestinal organoids, intestinal regeneration, intestinal stem cells, image-based screening, genetic interactions, retinoic acid signaling, retinoid X receptor, enterocyte differentiation, cell fate transitions, tissue homeostasis, retinoic acid metabolism, compound library screening
- MeSH terms
- Animals, Cell Differentiation, Homeostasis, Intestinal Mucosa, Intestines, Male, Mice, Inbred C57BL, Organoids, Phenotype, Regeneration, Transcription, Genetic, Tretinoin, Vitamin A, Signal Transduction, Sequence Analysis, RNA, Receptors, Retinoic Acid, Enterocytes, Mice
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