2. Academic Validation
  3. Establishment of intestinal organoid cultures modeling injury-associated epithelial regeneration

Establishment of intestinal organoid cultures modeling injury-associated epithelial regeneration

  • Cell Res. 2021 Mar;31(3):259-271. doi: 10.1038/s41422-020-00453-x.
Molong Qu # 1,  Liang Xiong # 1,  Yulin Lyu # 2,  Xiannian Zhang 3,  Jie Shen 3,  Jingyang Guan 1,  Peiyuan Chai 4,  Zhongqing Lin 5,  Boyao Nie 5,  Cheng Li 6,  Jun Xu 7,  Hongkui Deng 8 9
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100191, China.
  • 2 School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, 100871, China.
  • 3 Department of Neurobiology, Capital Medical University, Beijing, 100069, China.
  • 4 Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education and State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing, 100871, China.
  • 5 Beijing Vitalstar Biotechnology Co., Ltd, Beijing, 100000, China.
  • 6 School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, 100871, China. cheng_li@pku.edu.cn.
  • 7 School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100191, China. jun_xu@bjmu.edu.cn.
  • 8 School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100191, China. hongkui_deng@pku.edu.cn.
  • 9 State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, China. hongkui_deng@pku.edu.cn.
  • # Contributed equally.
PMID: 33420425 DOI: 10.1038/s41422-020-00453-x
Abstract

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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