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Original research
Reprogramming the spleen into a functioning ‘liver’ in vivo
  1. Chunyan Liu1,
  2. Lintao Wang1,2,
  3. Mengzhen Xu1,
  4. Yajie Sun1,
  5. Zhen Xing1,
  6. Junfeng Zhang1,
  7. Chunming Wang2,
  8. Lei Dong1,3
  1. 1 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
  2. 2 Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
  3. 3 Chemistry and Biomedicine Innovative Center, Nanjing University, Nanjing, Jiangsu, China
  1. Correspondence to Professor Lei Dong, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China; leidong{at}nju.edu.cn; Professor Chunming Wang, Taipa, Macau; cmwang{at}umac.mo; Professor Junfeng Zhang; jfzhang{at}nju.edu.cn

Abstract

Objective Liver regeneration remains one of the biggest clinical challenges. Here, we aim to transform the spleen into a liver-like organ via directly reprogramming the splenic fibroblasts into hepatocytes in vivo.

Design In the mouse spleen, the number of fibroblasts was through silica particles (SiO2) stimulation, the expanded fibroblasts were converted to hepatocytes (iHeps) by lentiviral transfection of three key transcriptional factors (Foxa3, Gata4 and Hnf1a), and the iHeps were further expanded with tumour necrosis factor-α (TNF-α) and lentivirus-mediated expression of epidermal growth factor (EGF) and hepatocyte growth factor (HGF).

Results SiO2 stimulation tripled the number of activated fibroblasts. Foxa3, Gata4 and Hnf1a converted SiO2-remodelled spleen fibroblasts into 2×106 functional iHeps in one spleen. TNF-α protein and lentivirus-mediated expression of EGF and HGF further enabled the total hepatocytes to expand to 8×106 per spleen. iHeps possessed hepatic functions—such as glycogen storage, lipid accumulation and drug metabolism—and performed fundamental liver functions to improve the survival rate of mice with 90% hepatectomy.

Conclusion Direct conversion of the spleen into a liver-like organ, without cell or tissue transplantation, establishes fundamental hepatic functions in mice, suggesting its potential value for the treatment of end-stage liver diseases.

  • liver regeneration
  • myofibroblasts
  • gene transfer

Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.

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Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.

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Footnotes

  • CL and LW are joint first authors.

  • Twitter @CM_Macau

  • CL and LW contributed equally.

  • Contributors LD conceived the study. LD, JZ and CW supervised the study. CL and LW designed the study, analysed data and performed a majority of experiments. MX, YS and ZX acquired and interpretated data. LD, CW and CL wrote the manuscript. All authors edited the manuscript. LD is responsible for the overall content as guarantor.

  • Funding This work was funded by the National Key Research and Development Programme of China (2017YFC0909700), the National Natural Science Foundation of China (31971309, 31671031, 32022088, 81973273, 81673380 and 32101093), the Jiangsu Province Funds for Distinguished Young Scientists (BK20170015), the Fundamental Research Funds for the Central Universities (020814380115), the China Postdoctoral Science Foundation (2020T130288). CW further acknowledges funding supports from the Science and Technology Development Fund, Macau SAR (File No. 0018/2019/AFJ) and the University of Macau Research Committee (MYRG2019-00080-ICMS). This study was also supported by the funds for the International Cooperation and Exchange of the Natural Science Foundation of China and the Science and Technology Development Fund (31961160701).

  • Competing interests None declared.

  • 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.