A glucose-blue light AND gate-controlled chemi-optogenetic cell-implanted therapy for treating type-1 diabetes in mice

Chi-Yu Li; Ting Wu; Xing-Jun Zhao; Cheng-Ping Yu; Zi-Xue Wang; Xiao-Fang Zhou; Shan-Ni Li; Jia-Da Li

doi:10.3389/fbioe.2023.1052607

A glucose-blue light AND gate-controlled chemi-optogenetic cell-implanted therapy for treating type-1 diabetes in mice

Front Bioeng Biotechnol. 2023 Feb 10:11:1052607. doi: 10.3389/fbioe.2023.1052607. eCollection 2023.

Authors

Chi-Yu Li^{1

2

3

4}, Ting Wu^{1

2

3

4}, Xing-Jun Zhao^{1

2

3

4}, Cheng-Ping Yu^{1

2

3

4}, Zi-Xue Wang^{1

2

3

4}, Xiao-Fang Zhou^{1

2

3

4}, Shan-Ni Li^{1

2

3

4}, Jia-Da Li^{1

2

3

4}

Affiliations

¹ Furong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
² Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China.
³ Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, China.
⁴ Hunan International Scientific and Technological Cooperation Base of Animal Models for Human Disease, Changsha, China.

Abstract

Exogenous insulin therapy is the mainstay treatment for Type-1 diabetes (T1D) caused by insulin deficiency. A fine-tuned insulin supply system is important to maintain the glucose homeostasis. In this study, we present a designed cell system that produces insulin under an AND gate control, which is triggered only in the presence of both high glucose and blue light illumination. The glucose-sensitive GIP promoter induces the expression of GI-Gal4 protein, which forms a complex with LOV-VP16 in the presence of blue light. The GI-Gal4:LOV-VP16 complex then promotes the expression of UAS-promoter-driven insulin. We transfected these components into HEK293T cells, and demonstrated the insulin was secreted under the AND gate control. Furthermore, we showed the capacity of the engineered cells to improve the blood glucose homeostasis through implantation subcutaneously into Type-1 diabetes mice.

Keywords: AND gate; cell-implanted therapy; chemigenetic; optogenetic; type-1 diabetes.

Grants and funding

This work was supported by the grants from the National Natural Science Foundation of China (31900392, 31972913), Hunan Provincial Natural Science Foundation of China (2021JJ30799), the China Postdoctoral Science Foundation (2019M652793), Fundamental Research Funds for the Central Universities of Central South University (CX20210178).