Quantitative evaluation of human bone mesenchymal stem cells rescuing fulminant hepatic failure in pigs.
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.
['Shi|Dongyan|D|', 'Zhang|Jianing|J|', 'Zhou|Qian|Q|', 'Xin|Jiaojiao|J|', 'Jiang|Jing|J|', 'Jiang|Longyan|L|', 'Wu|Tianzhou|T|', 'Li|Jiang|J|', 'Ding|Wenchao|W|', 'Li|Jun|J|', 'Sun|Suwan|S|', 'Li|Jianzhou|J|', 'Zhou|Ning|N|', 'Zhang|Liyuan|L|', 'Jin|Linfeng|L|', 'Hao|Shaorui|S|', 'Chen|Pengcheng|P|', 'Cao|Hongcui|H|', 'Li|Mingding|M|', 'Li|Lanjuan|L|', 'Chen|Xin|X|', 'Li|Jun|J|']
D000818:Animals D016026:Bone Marrow Transplantation D016207:Cytokines D004195:Disease Models, Animal D005688:Galactosamine D022781:Hepatocytes D006801:Humans D047908:Intracellular Signaling Peptides and Proteins D008099:Liver D017114:Liver Failure, Acute D008297:Male D008565:Membrane Proteins D045164:Mesenchymal Stem Cell Transplantation D019899:Paracrine Communication D051381:Rats D017207:Rats, Sprague-Dawley D015996:Survival Rate D013552:Swine
STEM CELLS FULMINANT HEPATIC FAILURE CYTOKINES