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Quantitative evaluation of human bone mesenchymal stem cells rescuing fulminant hepatic failure in pigs
  1. Dongyan Shi1,
  2. Jianing Zhang2,
  3. Qian Zhou1,
  4. Jiaojiao Xin1,
  5. Jing Jiang1,
  6. Longyan Jiang1,
  7. Tianzhou Wu1,
  8. Jiang Li1,
  9. Wenchao Ding1,
  10. Jun Li3,
  11. Suwan Sun1,
  12. Jianzhou Li1,
  13. Ning Zhou1,
  14. Liyuan Zhang1,
  15. Linfeng Jin1,
  16. Shaorui Hao1,
  17. Pengcheng Chen2,
  18. Hongcui Cao1,
  19. Mingding Li1,
  20. Lanjuan Li1,
  21. Xin Chen2,4,
  22. Jun Li1
  1. 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
  2. 2Institute of Biochemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
  3. 3Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
  4. 4Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto, Zhejiang University, Hangzhou, China
  1. Correspondence to Professor Jun Li, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd, Hangzhou 31000, China; lijun2009{at}zju.edu.cn Professor Xin Chen, Institute of Biochemistry, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Rd, Hangzhou, 310058. China; xinchen{at}zju.edu.cn Professor Lanjuan Li, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd, Hangzhou, 310003, China; ljli{at}zju.edu.cn

Abstract

Objective Stem cell transplantation provides a promising alternative for the treatment of fulminant hepatic failure (FHF). However, it lacks fundamental understanding of stem cells’ activities. Our objective was to clarify stem cell-recipient interactions for overcoming barriers to clinical application.

Design We used an in-house large-animal (pig) model of FHF rescue by human bone marrow mesenchymal stem cells (hBMSCs) and profiled the cells’ activities. The control and transplantation groups of pigs (n=15 per group) both received a D-galactosamine (D-Gal) injection (1.5 g/kg). The transplantation group received hBMSCs via intraportal vein infusion (3×106 cells/kg) immediately after D-Gal administration. The stem cell-recipient interactions were quantitatively evaluated by biochemical function, cytokine array, metabolite profiling, transcriptome sequencing and immunohistochemistry.

Results All pigs in the control group died within an average of 3.22 days, whereas 13/15 pigs in the transplantation group lived >14 days. The cytokine array and metabolite profiling analyses revealed that hBMSC transplantation suppressed D-Gal-induced life-threatening cytokine storms and stabilised FHF within 7 days, while human-derived hepatocytes constituted only ∼4.5% of the pig hepatocytes. The functional synergy analysis of the observed profile changes indicated that the implanted hBMSCs altered the pigs’ cytokine responses to damage through paracrine effects. Delta-like ligand 4 was validated to assist liver restoration in both pig and rat FHF models.

Conclusions Our results delineated an integrated model of the multifaceted interactions between stem cells and recipients, which may open a new avenue to the discovery of single molecule-based therapeutics that simulate stem cell actions.

  • STEM CELLS
  • FULMINANT HEPATIC FAILURE
  • CYTOKINES

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