Establishment of intestinal organoid cultures modeling injury-associated epithelial regeneration
Open accessAbstract
The capacity of 3D organoids to mimic physiological tissue organization and functionality has provided an invaluable tool to model development and disease in vitro. However, conventional organoid cultures primarily represent the homeostasis of self-organizing stem cells and their derivatives. Here, we established a novel intestinal organoid culture system composed of 8 components, mainly including VPA, EPZ6438, LDN193189, and R-Spondin 1 conditioned medium, which mimics the gut epithelium regeneration that produces hyperplastic crypts following injury; therefore, these organoids were designated hyperplastic intestinal organoids (Hyper-organoids). Single-cell RNA sequencing identified different regenerative stem cell populations in our Hyper-organoids that shared molecular features with in vivo injury-responsive Lgr5 + stem cells or Clu + revival stem cells. Further analysis revealed that VPA and EPZ6438 were indispensable for epigenome reprogramming and regeneration in Hyper-organoids, which functioned through epigenetically regulating YAP signaling. Furthermore, VPA and EPZ6438 synergistically promoted regenerative response in gut upon damage in vivo. In summary, our results demonstrated a new in vitro organoid model to study epithelial regeneration, highlighting the importance of epigenetic reprogramming that pioneers tissue repair.
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Significant differences in morphology, functionality, or organoid formation efficiency depend on the cells-of-origin, different cells in the organoid, and medium composition.
“Significant differences in morphology and functionality or even organoid formation efficiency depend on the different cells-of-origin of the culture or different cells in the organoid as well as different medium composition120,202–204.”
From Organoids (2022) · cites this paper as [120]
In Results, the paper reports that 8C versus ENR medium changes intestinal organoid morphology and regenerative behavior, and that Lgr5-GFP+ cells have higher organoid-forming efficiency than Lgr5-GFP− cells under 8C. The lineage-composition Results show different cells in the organoids, but do not establish that those differences cause the claimed changes in morphology, functionality, or formation efficiency. (LLM, conf=0.84)
Experimental — accuracy not yet measuredFujii et al. demonstrated that refining culture conditions could increase the diversity of differentiated cell fates in human small intestinal organoids.
“In that regard, a nice example was described by Fujii M et al. who demonstrated how refining of culture conditions could increase the diversity of differentiated cell fates in human small intestinal organoids120.”
From Organoids (2022) · cites this paper as [120]
The Results section reports that organoids grown under the new 8C culture condition contained multiple differentiated intestinal lineages, and Materials and methods describes culture supplements used to induce specific lineages (page numbers unavailable). But this paper is by Qu et al., not Fujii et al.; the cited passages do not demonstrate increased diversity of differentiated fates in human small intestinal organoids. (LLM, conf=0.78)
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- Authors
- Qu, M., Xiong, L., Lyu, Y., Zhang, X., Shen, J., Guan, J., Chai, P., Lin, Z., Nie, B., Li, C., Xu, J., & Deng, H.
- Affiliations
- Peking University (CN)
- Capital Medical University (CN)
- Corresponding author
- Li, Cheng
- Xu, Jun
- Deng, Hongkui
- ORCID
- Venue
- Cell Research
- Published
- 2021-01-08
- Volume
- 31
- Issue
- 3
- Pages
- 259-271
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- PMC
- PMC8027647
- OpenAlex
- W3119003316
- Cited by
- 138
- References
- 51
- Citations by year
- 2026: 21 · 2025: 31 · 2024: 41 · 2023: 18 · 2022: 21 · 2021: 6
- FWCI
- 6.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cell Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Greater South Information System
- Funders
- National Natural Science Foundation of China (31521004, 31871266, 2017YFA0103000, 31730059)
- Peking University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- intestinal organoids, epithelial regeneration, intestinal injury, valproic acid, LDN-193189, RSPO1, Lgr5+ stem cells, epigenetic reprogramming, YAP signaling, tissue repair, single-cell RNA sequencing
- MeSH terms
- Animals, Benzamides, Biphenyl Compounds, Cells, Cultured, Colitis, Disease Models, Animal, Female, Intestinal Mucosa, Intestines, Male, Mice, Inbred C57BL, Mice, Transgenic, Morpholines, Organoids, Pyridones, Radiation Injuries, Regeneration, Stem Cells, Valproic Acid, Signal Transduction, Dextran Sulfate, Treatment Outcome, Culture Media, Conditioned, Tissue Culture Techniques, Mice
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