RT Journal Article
SR Electronic
T1 Quantitative evaluation of human bone mesenchymal stem cells rescuing fulminant hepatic failure in pigs
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 955
OP 964
DO 10.1136/gutjnl-2015-311146
VO 66
IS 5
A1 Dongyan Shi
A1 Jianing Zhang
A1 Qian Zhou
A1 Jiaojiao Xin
A1 Jing Jiang
A1 Longyan Jiang
A1 Tianzhou Wu
A1 Jiang Li
A1 Wenchao Ding
A1 Jun Li
A1 Suwan Sun
A1 Jianzhou Li
A1 Ning Zhou
A1 Liyuan Zhang
A1 Linfeng Jin
A1 Shaorui Hao
A1 Pengcheng Chen
A1 Hongcui Cao
A1 Mingding Li
A1 Lanjuan Li
A1 Xin Chen
A1 Jun Li
YR 2017
UL http://gut.bmj.com/content/66/5/955.abstract
AB 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.