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J Hepatol. 2016 Jul;65(1):84-94. doi: 10.1016/j.jhep.2016.03.020. Epub 2016 Apr 9.

A synthetic biology-based device prevents liver injury in mice.

Author information

1
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.
2
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
3
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland; Faculty of Medicine, University of Basel, Petersgraben 4, CH-4031 Basel, Switzerland; Division of Endocrinology and Diabetes, Stadtspital Triemli, Birmensdorferstrasse 497, CH-8063 Zurich, Switzerland.
4
Département Génie Biologique, Université Claude Bernard 1, 43 Boulevard du 11 Novembre 1918, F-69100 Villeurbanne, France.
5
Institute of Anatomy, University of Berne, Baltzerstrasse 2, CH-3000 Berne, Switzerland.
6
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland; Faculty of Science, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland. Electronic address: fussenegger@bsse.ethz.ch.

Abstract

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.

KEYWORDS:

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

PMID:
27067456
PMCID:
PMC4914822
DOI:
10.1016/j.jhep.2016.03.020
[Indexed for MEDLINE]
Free PMC Article

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