A synthetic biology-based device prevents liver injury in mice

详细信息    查看全文

• 作者：Peng Bai¹ ; Haifeng Ye¹ ; ² ; Mingqi Xie¹ ; Pratik Saxena¹ ; Henryk Zulewski¹ ; ³ ; ⁴ ; Ghislaine Charpin-El Hamri⁵ ; Valentin Djonov⁶ ; Martin Fussenegger¹ ; ⁷ ; ^{fussenegger@bsse.ethz.ch" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HGF ; hepatocyte growth factor ; PKA ; cAMP-dependent phosphokinase A ; CRE ; cAMP-response element ; PCRE ; CRE-containing synthetic mammalian promoter ; SEAP ; human placental secreted alkaline phosphatase ; CREm ; modified cAMP-response element ; PCREm ; modified PCRE variant ; TUDCA ; tauroursodeoxycholic acid ; shGLP1 ; short human glucacon-like peptide 1 ; SBA ; serum bile acid ; CCl4 ; Carbon tetrachloride ; ANIT ; alpha-naphthylisothiocyanate
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：65
• 期：1
• 页码：84-94
• 全文大小：2264 K

文摘

The liver performs a panoply of complex activities coordinating metabolic, immunologic and detoxification processes. Despite the liver’s robustness and unique self-regeneration capacity, viral infection, autoimmune disorders, fatty liver disease, alcohol abuse and drug-induced hepatotoxicity contribute to the increasing prevalence of liver failure. Liver injuries impair the clearance of bile acids from the hepatic portal vein which leads to their spill over into the peripheral circulation where they activate the G-protein-coupled bile acid receptor TGR5 to initiate a variety of hepatoprotective processes.

Methods

By functionally linking activation of ectopically expressed TGR5 to an artificial promoter controlling transcription of the hepatocyte growth factor (HGF), we created a closed-loop synthetic signalling network that coordinated liver injury-associated serum bile acid levels to expression of HGF in a self-sufficient, reversible and dose-dependent manner.

Results

After implantation of genetically engineered human cells inside auto-vascularizing, immunoprotective and clinically validated alginate-poly-(L-lysine)-alginate beads into mice, the liver-protection device detected pathologic serum bile acid levels and produced therapeutic HGF levels that protected the animals from acute drug-induced liver failure.

Conclusions

Genetically engineered cells containing theranostic gene circuits that dynamically interface with host metabolism may provide novel opportunities for preventive, acute and chronic healthcare.

Lay summary

Liver diseases leading to organ failure may go unnoticed as they do not trigger any symptoms or significant discomfort. We have designed a synthetic gene circuit that senses excessive bile acid levels associated with liver injuries and automatically produces a therapeutic protein in response. When integrated into mammalian cells and implanted into mice, the circuit detects the onset of liver injuries and coordinates the production of a protein pharmaceutical which prevents liver damage.