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. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000116099Publication status
publishedExternal links
Journal / series
Journal of HepatologyVolume
Pages / Article No.
Publisher
ElsevierSubject
Genetically engineered cells; Gene- and cell-based therapy; Liver disease; Regeneration; Synthetic biology; Synthetic gene circuitsOrganisational unit
03694 - Fussenegger, Martin / Fussenegger, Martin
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