Quantitative evaluation of human bone mesenchymal stem cells rescuing fulminant hepatic failure in pigs.

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.

• Authors: Dongyan Shi, Jianing Zhang, Qian Zhou, Jiaojiao Xin, Jing Jiang, Longyan Jiang, Tianzhou Wu, Jiang Li, Wenchao Ding, Jun Li, Suwan Sun, Jianzhou Li, Ning Zhou, Liyuan Zhang, Linfeng Jin, Shaorui Hao, Pengcheng Chen, Hongcui Cao, Mingding Li, Lanjuan Li, Xin Chen, Jun Li
• Journal: Gut (Gut) Vol. 66 Issue 5 Pg. 955-964 (05 2017) ISSN: 1468-3288 [Electronic] England
• PMID: 26884426 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Chemical References

• Cytokines
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• delta protein
• Galactosamine

Topics

• Animals
• Bone Marrow Transplantation
• Cytokines (blood)
• Disease Models, Animal
• Galactosamine (pharmacology)
• Hepatocytes
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Liver (pathology)
• Liver Failure, Acute (metabolism, pathology, therapy)
• Male
• Membrane Proteins (metabolism)
• Mesenchymal Stem Cell Transplantation
• Paracrine Communication
• Rats
• Rats, Sprague-Dawley
• Survival Rate
• Swine