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Deep-tissue high-sensitivity multimodal imaging and optogenetic manipulation enabled by biliverdin reductase
Ludmila A Kasatkina1, Chenshuo Ma2, Huaxin Sheng3
1Department of Genetics and Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Nature Communications
|July 14, 2025
Summary
A new mouse model with elevated biliverdin levels significantly enhances bacterial phytochrome-based optogenetic tools and deep-tissue imaging capabilities. This breakthrough improves light-controlled gene expression and insulin production for potential therapeutic applications.
Area of Science:
- Biophysics
- Molecular Biology
- Optogenetics
Background:
- Bacterial phytochrome-derived near-infrared probes and optogenetic tools require biliverdin chromophore for optimal performance.
- Limited biliverdin availability restricts the efficacy of these advanced biological tools.
Purpose of the Study:
- To enhance the performance of bacterial phytochrome-based systems by increasing endogenous biliverdin levels.
- To develop improved deep-tissue imaging and optogenetic manipulation strategies using a novel mouse model.
Main Methods:
- Utilized a biliverdin reductase-A knock-out mouse model (Blvra-/-) to elevate endogenous biliverdin.
- Assessed light-controlled transcription with the iLight optogenetic tool in Blvra-/- cells and neurons.
- Investigated light-induced insulin production in Blvra-/- mice for diabetes management.
- Employed 3D photoacoustic, ultrasound, and two-photon fluorescence microscopy for deep-tissue imaging.
Main Results:
- Blvra-/- cells showed a ~25-fold improvement in iLight-driven transcription compared to wild-type.
- Optogenetic activation in neurons achieved ~100-fold enhancement in Blvra-/- models.
- Insulin production in Blvra-/- mice reduced blood glucose by ~60% in a diabetes model.
- Achieved deep-tissue imaging at ~7 mm depth using photoacoustic and ultrasound microscopy, and ~2.2 mm with two-photon microscopy.
Conclusions:
- The Blvra-/- mouse model significantly boosts the efficacy of biliverdin-dependent optogenetic tools and imaging probes.
- This model offers a powerful platform for advancing deep-tissue imaging and optogenetic applications in neuroscience and metabolic disease research.
