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

被引：132

作者：

Shi, Dongyan ^{[1
]}

Zhang, Jianing ^{[2
]}

Zhou, Qian ^{[1
]}

Xin, Jiaojiao ^{[1
]}

Jiang, Jing ^{[1
]}

Jiang, Longyan ^{[1
]}

Wu, Tianzhou ^{[1
]}

Li, Jiang ^{[1
]}

Ding, Wenchao ^{[1
]}

Li, Jun ^{[1
,3
]}

Sun, Suwan ^{[1
]}

Li, Jianzhou ^{[1
]}

Zhou, Ning ^{[1
]}

Zhang, Liyuan ^{[1
]}

Jin, Linfeng ^{[1
]}

Hao, Shaorui ^{[1
]}

Chen, Pengcheng ^{[2
]}

Cao, Hongcui ^{[1
]}

Li, Mingding ^{[1
]}

Li, Lanjuan ^{[1
]}

Chen, Xin ^{[2
,4
]}

Li, Jun ^{[1
,3
]}

机构：

[1] Zhejiang Univ, Affiliated Hosp 1, Collaborat Innovat Ctr Diag & Treatment Infect Di, State Key Lab Diag & Treatment Infect Dis,Sch Med, 79 Qingchun Rd, Hangzhou 31000, Zhejiang, Peoples R China

[2] Zhejiang Univ, Coll Pharmaceut Sci, Inst Biochem, 866 Yuhangtang Rd, Hangzhou 310058, Zhejiang, Peoples R China

[3] Zhejiang Univ, Affiliated Hosp 1, Dept Pathol, Sch Med, Hangzhou, Zhejiang, Peoples R China

[4] Zhejiang Univ, Joint Inst Genet & Genome Med Zhejiang Univ & Uni, Hangzhou, Zhejiang, Peoples R China

来源：

GUT | 2017年 / 66卷 / 05期

基金：

中国国家自然科学基金;

关键词：

MYOCARDIAL-INFARCTION; LIVER-REGENERATION; PARACRINE FACTORS; THERAPIES; MECHANISMS; REPAIR; KIT;

D O I：

10.1136/gutjnl-2015-311146

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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.

引用

页码：955 / 964

页数：10

共 33 条

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