Far-red light-activated human islet-like designer cells enable sustained fine-tuned secretion of insulin for glucose control

• Published in: Molecular therapy Vol. 30; no. 1; pp. 341 - 354
• Main Authors: Yu, Guiling, Zhang, Mingliang, Gao, Ling, Zhou, Yang, Qiao, Longliang, Yin, Jianli, Wang, Yiwen, Zhou, Jian, Ye, Haifeng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.01.2022; American Society of Gene & Cell Therapy
• Subjects: Animals; Blood Glucose; blood glucose control; cell therapy; Diabetes Mellitus, Type 1 - therapy; Diabetes Mellitus, Type 2; far-red light; Humans; Insulin - metabolism; Insulin Secretion; Mice; optogenetics; Original; oxidative stress; renal damage; synthetic designer cell; type 1 diabetes; type 1 diabetes; far-red light; cell therapy; optogenetics; synthetic designer cell; blood glucose control; oxidative stress; renal damage
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2021.09.004

Diabetes affects almost half a billion people, and all individuals with type 1 diabetes (T1D) and a large portion of individuals with type 2 diabetes rely on self-administration of the peptide hormone insulin to achieve glucose control. However, this treatment modality has cumbersome storage and equipment requirements and is susceptible to fatal user error. Here, reasoning that a cell-based therapy could be coupled to an external induction circuit for blood glucose control, as a proof of concept we developed far-red light (FRL)-activated human islet-like designer (FAID) cells and demonstrated how FAID cell implants achieved safe and sustained glucose control in diabetic model mice. Specifically, by introducing a FRL-triggered optogenetic device into human mesenchymal stem cells (hMSCs), which we encapsulated in poly-(l-lysine)-alginate and implanted subcutaneously under the dorsum of T1D model mice, we achieved FRL illumination-inducible secretion of insulin that yielded improvements in glucose tolerance and sustained blood glucose control over traditional insulin glargine treatment. Moreover, the FAID cell implants attenuated both oxidative stress and development of multiple diabetes-related complications in kidneys. This optogenetics-controlled “living cell factory” platform could be harnessed to develop multiple synthetic designer therapeutic cells to achieve long-term yet precisely controllable drug delivery. [Display omitted] Haifeng Ye and his colleagues described far-red light-responsive designer cells engineered for blood glucose control. They showed that implantation of these cells and daily illumination offers long-term control of blood glucose in diabetic mice. This optogenetic designer cell technology confers protection against both diabetes-associated oxidative stress and kidney damage.