Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Mol Ther. 2022 Jan 5;30(1):341-354. doi: 10.1016/j.ymthe.2021.09.004. Epub 2021 Sep 14.
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.
糖尿病影响了近 5 亿人，所有 1 型糖尿病（T1D）患者和很大一部分 2 型糖尿病患者都依赖于自行注射肽类激素胰岛素来实现血糖控制。然而，这种治疗方式具有繁琐的存储和设备要求，并且容易发生致命的用户错误。在这里，我们推断细胞疗法可以与外部感应电路相结合，用于血糖控制，作为概念验证，我们开发了远红激光（FRL）激活的人胰岛样设计（FAID）细胞，并展示了 FAID 细胞植入物如何在糖尿病模型小鼠中实现安全和持续的血糖控制。具体来说，我们通过将 FRL 触发的光遗传学装置引入人间充质干细胞（hMSC）中，将其封装在聚（L-赖氨酸）-海藻酸钠中，并植入 T1D 模型小鼠背部的皮下，实现了 FRL 光照诱导的胰岛素分泌，从而改善了葡萄糖耐量，并在传统胰岛素甘精治疗的基础上持续控制血糖。此外，FAID 细胞植入物减轻了肾脏中氧化应激和多种与糖尿病相关并发症的发展。这个光遗传学控制的“活细胞工厂”平台可以被利用来开发多种合成设计治疗细胞，以实现长期但精确可控的药物输送。
