Abstract
Body temperature is maintained at around 37 °C in humans, but may rise to 40 °C or more during high‐grade fever, which occurs in most adults who are seriously ill. However, endogenous temperature sensors, such as ion channels and heat‐shock promoters, are fully activated only at noxious temperatures above this range, making them unsuitable for medical applications. Here, a genetically encoded protein thermometer (human enhanced gene activation thermometer; HEAT) is designed that can trigger transgene expression in the range of 37–40 °C by linking a mutant coiled‐coil temperature‐responsive protein sensor to a synthetic transcription factor. To validate the construct, a HEAT‐transgenic monoclonal human cell line, FeverSense, is generated and it is confirmed that it works as a fever sensor that can temperature‐ and exposure‐time‐dependently trigger reporter gene expression in vitro and in vivo. For translational proof of concept, microencapsulated designer cells stably expressing a HEAT‐controlled insulin production cassette in a mouse model of type‐1 diabetes are subcutaneously implanted and topical heating patches are used to apply heat corresponding to a warm sensation in humans. Insulin release is induced, restoring normoglycemia. Thus, HEAT appears to be suitable for practical electrothermal control of cell‐based therapy, and may also have potential for next‐generation treatment of fever‐associated medical conditions.
Highlights
This page was generated automatically upon download from the ETH Zurich Research Collection
Wild-type mice, subcutaneously implanted with engineered cells for heat-shock promoter-driven secreted alkaline phosphatase (SEAP) expression, whose skin surface temperature was increased to 44 °C by infrared illumination or topical heat patches, showed only modestly increased blood SEAP levels (Figure S1e, Supporting Information), suggesting that the animals’ homeostatic control compensated for external heating of the skin
These results suggest that orthogonal temperature-inducible transgene regulation remains challenging in living animals and likely requires genetically encoded temperature sensors to operate much closer to the homeostatic temperature.[36,37]
Summary
This page was generated automatically upon download from the ETH Zurich Research Collection. A genetically encoded protein thermometer (human short-term environmental temperature enhanced gene activation thermometer; HEAT) is designed that can trigger transgene expression in the range of 37–40 °C by linking a mutant coiled-coil temperature-responsive protein sensor to a synthetic transcription factor. FeverSense, is generated and it is confirmed that it works as a fever sensor perature shifts.[3,4] For this purpose, the that can temperature- and exposure-time-dependently trigger reporter gene hypothalamus acts as central thermostat expression in vitro and in vivo. For translational proof of concept, microencapsulated designer cells stably expressing a HEAT-controlled insulin production cassette in a mouse model of type-1 diabetes are subcutaneously implanted and topical heating patches are used to apply heat corresponding by integrating temperature inputs from cold- and heat-sensitive neuronal fibers that collect information from thermal sensors, such as cold-activated (TRPA1, TRPM8) and heat-activated (TRPV1, TRPM2, TRPM3)
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