Far-red light-activated human islet-like designer cells enable sustained fine-tuned secretion of insulin for glucose control in T1D mice.
Far-red light-activated human islet-like designer cells enable sustained fine-tuned secretion of insulin for glucose control in T1D mice.
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DOI：
10.1016/j.ymthe.2021.09.004
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发表时间：
2021-09
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通讯作者：
Gui-Na Yu;Mingliang Zhang;Ling Gao;Yang Zhou;Longliang Qiao;Jianli Yin;Yiwen Wang;Jian Zhou;Haifeng Ye
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作者：
Gui-Na Yu;Mingliang Zhang;Ling Gao;Yang Zhou;Longliang Qiao;Jianli Yin;Yiwen Wang;Jian Zhou;Haifeng Ye
糖尿病影响着近5亿人，所有1型糖尿病（T1 D）患者和大部分2型糖尿病患者都依赖于自我施用肽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，推理基于细胞的治疗可以耦合到外部诱导电路用于血糖控制，作为概念的证明，我们开发了远红光（FRL）激活的人类胰岛样设计者（FAID）细胞，并证明了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葡萄糖控制。具体而言，通过将FRL触发的光遗传学装置引入人间充质干细胞（hMSC）中，我们将其封装在聚-（l-赖氨酸）-藻酸盐中并皮下植入T1 D模型小鼠的背部下，我们实现了FRL照明诱导的胰岛素分泌，其产生了葡萄糖耐量的改善，并且与传统的甘精胰岛素治疗相比持续血糖控制。此外，FAID细胞植入物减弱了肾脏中氧化应激和多种糖尿病相关并发症的发展。这种光遗传学控制的“活细胞工厂”平台可以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。
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.