Engineering of optogenetic designer human cells for diabetes therapy

Could combating diabetes lie in as simple as a beam of light? This scenario might not sound to be a fiction due to the breakthrough research in optogenetics. In this scientific research area, genetically encoded photosensors translate light signal into specifically engineered biological processes, such as programming signalling pathways and transgene expression by the control of light. In our former research, we have successfully developed a blue-light-controlled transgene expression device for controlling of blood glucose homeostasis in diabetic mice. Although several potent light-triggered transcriptional gene switches have been characterized in mammalian cells over the past five years, important parameters such as light source, illumination strength and stimulation frequency must be carefully chosen in regard to biomedical applications involving living animals. For example, continuous exposure of mammalian cells to blue light is often cytotoxic, reducing the gene expression capacity of transfected cells. In this regard, far-red light (FRL) is a biocompatible light source which has been exploited for several decades by physiotherapy infrared lamps because of its ability to deeply penetrate into tissues. Here we will report a synthetic FRL-controlled optogenetic switch that enables programming transgene expression in human cells and mice. The synthetic optogenetic signaling pathway consists of an engineered FRL-triggered synthesis of cyclic diguanylate monophosphate (c-di-GMP), which further activates of synthetic hybrid promoters. This synthetic optogenetic device achieved more than 200-fold photoactivation of transgene expression in human cells. The optogenetic implant containing designer cells engineered for FRL-adjustable expression of insulin and glucagon-like peptide 1 (GLP-1) was able to lower blood glucose both in type I and type II diabetic mice. Synthetic biology-inspired phototherapy devices for traceless spatiotemporal control of transgene expression may provide new treatment opportunities for gene- and cellbased therapies in the future.