Journal
GUT
Volume 66, Issue 5, Pages 955-964Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2015-311146
Keywords
-
Categories
Funding
- National Basic Research Program of China [2012CB944900]
- Zhejiang Provincial and National Natural Science Foundation of China [LR13H030001, LR13C020001, 81271708, 81571818, 31571356]
- Chinese High Tech Research and Development (863) Program [2013AA020102]
- National ST Major Project [2012ZX10004503-006, 2012ZX10002004-001]
- Research Fund for the Doctoral Program of Higher Education [20130101110008]
Ask authors/readers for more resources
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 (3x106 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 similar to 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available