A programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells.
A programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells.
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DOI：
10.1038/ncomms11247
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发表时间：
2016-04-11
影响因子：
16.6
通讯作者：
Fussenegger M
中科院分区：
文献类型：
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作者：
Saxena P;Heng BC;Bai P;Folcher M;Zulewski H;Fussenegger M
合成生物学已经推进了对细胞行为进行编程的标准化转录控制装置的设计。通过将基于合成信号级联和转录因子的基因开关与对许可食品添加剂香草酸的反向和差异敏感性相结合，我们设计了一个合成谱系控制网络，该网络结合了香草酸触发的转录因子Ngn 3的互斥表达开关。（神经生成素3;关-开-关）和Pdx 1（胰腺和十二指肠同源框1;开-关-开）与MafA（V-maf肌肉腱膜纤维肉瘤癌基因同源物A;关-开）的伴随诱导。这种设计师网络由不同的网络拓扑结构组成，协调及时控制转基因和基因组Ngn3，Pdx 1和MafA变体，能够将人类诱导多能干细胞（hIPSC）衍生的胰腺祖细胞编程为葡萄糖敏感的胰岛素分泌β样细胞，其葡萄糖刺激的胰岛素释放动力学与人类胰岛相当。合成谱系控制网络可能提供缺失的环节，将体细胞遗传编程为再生医学的自体细胞表型。 合成生物学为设计和实施合理设计的复杂遗传方案提供了可能性。在这里，作者设计了一个遗传网络来触发患者来源的IPSC分化为β样细胞。
Synthetic biology has advanced the design of standardized transcription control devices that programme cellular behaviour. By coupling synthetic signalling cascade- and transcription factor-based gene switches with reverse and differential sensitivity to the licensed food additive vanillic acid, we designed a synthetic lineage-control network combining vanillic acid-triggered mutually exclusive expression switches for the transcription factors Ngn3 (neurogenin 3; OFF-ON-OFF) and Pdx1 (pancreatic and duodenal homeobox 1; ON-OFF-ON) with the concomitant induction of MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A; OFF-ON). This designer network consisting of different network topologies orchestrating the timely control of transgenic and genomic Ngn3, Pdx1 and MafA variants is able to programme human induced pluripotent stem cells (hIPSCs)-derived pancreatic progenitor cells into glucose-sensitive insulin-secreting beta-like cells, whose glucose-stimulated insulin-release dynamics are comparable to human pancreatic islets. Synthetic lineage-control networks may provide the missing link to genetically programme somatic cells into autologous cell phenotypes for regenerative medicine. Synthetic biology offers the potential for the design and implementation of rationally designed, complex genetic programmes. Here the authors design a genetic network to trigger the differentiation of patient derived IPSCs into beta-like cells.