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Hepatology
Original research
Bioprinting functional hepatocyte organoids derived from human chemically induced pluripotent stem cells to treat liver failure
  1. Guangya Li1,
  2. Jianyu He2,3,4,
  3. Jihang Shi5,
  4. Xinyi Li6,
  5. Lulu Liu7,
  6. Xinlan Ge8,
  7. Wenhan Chen1,
  8. Jun Jia9,
  9. Jinlin Wang10,
  10. Ming Yin11,
  11. Yasuyuki Sakai12,
  12. Wei Sun2,3,4,13,
  13. Hongkui Deng1,9,14,
  14. Yuan Pang2,3,4
  1. 1Ministry of Education (MOE) Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, People's Republic of China
  2. 2Biomanufacturing Center, Department of Mechanical Engineering, Tsinghua University, Beijing, People's Republic of China
  3. 3Biomanufacturing and Rapid Forming Technology Key Laboratory of Beijing, Tsinghua University, Beijing, People's Republic of China
  4. 4Key Laboratory for Advanced Materials Processing Technology, Ministry of Education, Beijing, People's Republic of China
  5. 5Department of Gastroenterology, The Second Medical Center of PLA General Hospital, Chinese PLA General Hospital, Beijing, People's Republic of China
  6. 6International Cancer Institute, Peking University Health Science Center, Beijing, People's Republic of China
  7. 7Peking University-Tsinghua University-National Institute of Biological Science Joint Graduate Program, Academy for Advanced Interdisciplinary Studies, Beijing, People's Republic of China
  8. 8Department of Hepatobiliary Surgery, Chinese PLA General Hospital, PLA, Beijing, People's Republic of China
  9. 9Beijing Changping Laboratory, Beijing, People's Republic of China
  10. 10Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, People's Republic of China
  11. 11Beijing Vitalstar Biotechnology, Beijing, People's Republic of China
  12. 12Department of Chemical System Engineering, Graduate School of Engineering, University of Tokyo, Tokyo, Japan
  13. 13Department of Mechanical Engineering and Mechanics, College of Engineering, Drexel University, Philadelphia, Pennsylvania, USA
  14. 14MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, People's Republic of China
  1. Correspondence to Professor Yuan Pang; pangyuan31{at}tsinghua.edu.cn; Professor Hongkui Deng; hongkui_deng{at}pku.edu.cn

Abstract

Background To treat liver failure, three-dimensional (3D) bioprinting is a promising technology used to construct hepatic tissue models. However, current research on bioprinting of hepatic tissue models primarily relies on conventional single-cell-based bioprinting, where individual functional hepatocytes are dispersed and isolated within hydrogels, leading to insufficient treatment outcomes due to inadequate cell functionality.

Objective Here, we aim to bioprint a hepatic tissue model using functional hepatocyte organoids (HOs) and evaluate its liver-specific functions in vitro and in vivo.

Design Human chemically induced pluripotent stem cells (hCiPSCs) were used as a robust and non-genome-integrative cell source to produce highly viable and functional HOs (hCiPSC-HOs). An oxygen-permeable microwell device was used to enhance oxygen supply, ensuring high cell viability and promoting hCiPSC-HOs maturation. To maintain the long-term biofunction of hCiPSC-HOs, spheroid-based bioprinting was employed to construct hepatic tissue models (3DP-HOs). 3DP-HOs were intraperitoneally implanted in mice with liver failure.

Results 3DP-HOs demonstrated enhanced cell viability when compared with a model fabricated using single-cell-based bioprinting and exhibited gene profiles closely resembling hCiPSC-HOs while maintaining liver-specific functionality. Moreover, 3DP-HOs implantation significantly improved survival in mice with CCl4-induced acute-on-chronic liver failure and also Fah−/− mice with liver failure. 3DP-HOs significantly reduced liver injury, inflammation and fibrosis indices while promoting liver regeneration and biofunction expression.

Conclusion Our bioprinted hepatic tissue model exhibits remarkable therapeutic efficacy for liver failure and holds great potential for clinical research in the field of liver regenerative medicine.

  • LIVER FAILURE
  • HEPATOCYTE
  • LIVER

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/gutjnl-2024-333885

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • GL and JH are joint first authors.

    • GL and JH contributed equally.

    • Contributors YP, HD and WS conceived of the project. GL, JH wrote the manuscript. GL, JH, JS performed the experiments, collected and analyzed the data. XL and WC performed the analysis of bulk RNA-seq data. LL, JJ, JW, YP, WS, YS and HD revised the manuscript. XG performed the transplantation of 3D printed scaffolds into mice. MY provided Fah–/– mice. JS provided human primary hepatocytes. All authors have contributed to the manuscript and approved the submitted version. YP is responsible for the overall content as guarantor.

    • Funding This work was supported by the National Key Research and Development Program of China (2021YFF1201100), National Natural Science Foundation of China (32270603, 32288102, 52175273, 52211540006 and 52422508), the Beijing Nova Program (20220484075), the Tsinghua University Initiative Scientific Research Program (2022ZLB004), Beijing Science and Technology Plan No.Z231100007223006, the Natural Science Foundation of Chongqing (2022NSCQ- LZX0326), the 111 Project (B17026) and Changping Laboratory.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.