Light-stimulated insulin secretion from pancreatic islet-like organoids derived from human pluripotent stem cells

被引:13
作者
Choi, Jieun [1 ]
Shin, Eunji [1 ]
Lee, Jinsu [1 ]
Devarasou, Somayadineshraj [2 ]
Kim, Dongkyu [1 ]
Shin, Jennifer H. [2 ]
Choi, Jin-Ho [3 ]
Do Heo, Won [1 ]
Han, Yong -Mahn [1 ,4 ]
机构
[1] Korea Adv Inst Sci & Technol, Dept Biol Sci, Daejeon 34141, South Korea
[2] Korea Adv Inst Sci & Technol, Dept Mech Engn, Daejeon 34141, South Korea
[3] Univ Ulsan, Asan Med Ctr, Dept Pediat, Coll Med, Seoul 05505, South Korea
[4] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon 34141, South Korea
关键词
K-ATP CHANNEL; BETA-CELL; IN-VITRO; OPTOGENETIC CONTROL; CHANNELRHODOPSIN-2; REPLACEMENT; GENERATION; STRATEGIES; INDUCTION; MECHANISM;
D O I
10.1016/j.ymthe.2023.03.013
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Optogenetic techniques permit non-invasive, spatiotemporal, and reversible modulation of cellular activities. Here, we report a novel optogenetic regulatory system for insulin secretion human pluripotent stem cell (hPSC)-derived pancreatic islet like organoids using monSTIM1 (monster-opto-Stromal interaction molecule 1), an ultra-light-sensitive OptoSTIM1 variant. The monSTIM1 transgene was incorporated at AAVS1 locus in human embryonic stem cells (hESCs) CRISPR-Cas9-mediated genome editing. Not only were able to elicit light-induced intracellular Ca2+ concentration ([Ca2+]i) transients from the resulting homozygous monSTIM1+/+-hESCs, but we also successfully differentiated them into pancreatic islet-like organoids (PIOs). Upon light stimulation, the b-cells in these monSTIM1+/+-PIOs displayed reversible and reproducible [Ca2+]i transient dynamics. Furthermore, in response to photoexcitation, they secreted man insulin. Light-responsive insulin secretion was similarly observed in monSTIM1+/+-PIOs produced from neonatal betes (ND) patient-derived induced pluripotent stem cells (iPSCs). Under LED illumination, monSTIM1+/+-PIO-trans-planted diabetic mice produced human c-peptide. Collectively, we developed a cellular model for the optogenetic control of sulin secretion using hPSCs, with the potential to be applied the amelioration of hyperglycemic disorders.
引用
收藏
页码:1480 / 1495
页数:16
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