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Theranostics 2021; 11(11):5569-5584. doi:10.7150/thno.53883 This issue Cite

Research Paper

Direct optogenetic stimulation of smooth muscle cells to control gastric contractility

Markus Vogt¹, Benjamin Schulz², Ahmed Wagdi¹, Jan Lebert³, Gijsbert J. van Belle¹, Jan Christoph^3,4, Tobias Bruegmann^1✉, Robert Patejdl^2✉

1. Institute of Cardiovascular Physiology, University Medical Center Göttingen, Humboldtallee 23, 37073 Göttingen, Germany.
2. Oscar Langendorff Institute for Physiology, University of Rostock, Germany.
3. Department of Cardiology and Pneumology, University Medical Center Göttingen, Robert-Koch-Str. 42a-Heart Research Building, 37075 Göttingen, Germany.
4. Current address: Cardiovascular Research Institute, University of California, San Francisco, 555 Mission Bay Blvd South, San Francisco, CA 94158, USA.

✉ Corresponding authors: Tobias Brügmann & Robert Patejdl contributed equally to this work. Tobias Brügmann, Institute for Cardiovascular Physiology, Humboldtallee 23, 37073 Göttingen. E-mail: tobias.bruegmannuni-goettingen.de; Tel.: +49 (0)551 39 5896; Fax: +49 (0)551 39 5895; Robert Patejdl, Oscar Langendorff Institute for Physiology, Gertrudenstraße 9, 18057 Rostock. E-mail: robert.patejdlde; Tel.: +49 (0)381 494 8006; Fax: +49 (0)381 494 8001. More

Abstract

Rationale: Antral peristalsis is responsible for gastric emptying. Its failure is called gastroparesis and often caused by dysfunction of enteric neurons and interstitial cells of Cajal (ICC). Current treatment options, including gastric electrical stimulation, are non-satisfying and may improve symptoms but commonly fail to restore gastric emptying. Herein, we explore direct optogenetic stimulation of smooth muscle cells (SMC) via the light-gated non-selective cation channel Channelrhodopsin2 (ChR2) to control gastric motor function.

Methods: We used a transgenic mouse model expressing ChR2 in fusion with eYFP under the control of the chicken-β-actin promoter. We performed patch clamp experiments to quantify light-induced currents in isolated SMC, Ca²⁺ imaging and isometric force measurements of antral smooth muscle strips as well as pressure recordings of intact stomachs to evaluate contractile responses. Light-induced propulsion of gastric contents from the isolated stomach preparation was quantified in video recordings. We furthermore tested optogenetic stimulation in a gastroparesis model induced by neuronal- and ICC-specific damage through methylene blue photo-toxicity.

Results: In the stomachs, eYFP signals were restricted to SMC in which blue light (460 nm) induced inward currents typical for ChR2. These depolarizing currents led to contractions in antral smooth muscle strips that were stronger than those triggered by supramaximal electrical field stimulation and comparable to those evoked by global depolarization with high K⁺ concentration. In the intact stomach, panoramic illumination efficiently increased intragastric pressure achieving 239±46% (n=6) of the pressure induced by electrical field stimulation and triggered gastric transport. Within the gastroparesis model, electric field stimulation completely failed but light still efficiently generated pressure waves.

Conclusions: We demonstrate direct optogenetic stimulation of SMC to control gastric contractility. This completely new approach could allow for the restoration of motility in gastroparesis in the future.

Keywords: optogenetics, gastric motility, gastroparesis, smooth muscle, channelrhodopsin

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