A synthetic biology-based device prevents liver injury in mice

Bai, Peng; Ye, Haifeng; Xie, Mingqi; Saxena, Pratik; Zulewski, Henryk; Charpin-El Hamri, Ghislaine; Djonov, Valentin; Fussenegger, Martin (2016). A synthetic biology-based device prevents liver injury in mice. Journal of hepatology, 65(1), pp. 84-94. Elsevier 10.1016/j.jhep.2016.03.020

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BACKGROUND & AIMS 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy

UniBE Contributor:

Djonov, Valentin

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0168-8278

Publisher:

Elsevier

Language:

English

Submitter:

Ruslan Hlushchuk

Date Deposited:

12 Jul 2016 13:30

Last Modified:

13 Jul 2016 22:11

Publisher DOI:

10.1016/j.jhep.2016.03.020

PubMed ID:

27067456

Uncontrolled Keywords:

Gene- and cell-based therapy; Genetically engineered cells; Liver disease; Regeneration; Synthetic biology; Synthetic gene circuits

BORIS DOI:

10.7892/boris.82611

URI:

https://boris.unibe.ch/id/eprint/82611

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