Combined small molecule treatment accelerates timing of maturation in human pluripotent stem cell-derived neurons
Combined small molecule treatment accelerates timing of maturation in human pluripotent stem cell-derived neurons
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联合小分子治疗可加速人类多能干细胞衍生神经元的成熟时间
DOI：
10.1101/2022.06.02.494616
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
L. Studer
中科院分区：
文献类型：
--
作者：
Emiliano Hergenreder;Yana Zorina;Zeping Zhao;H. Munguba;Elizabeth L. Calder;A. Baggiolini;Andrew P. Minotti;R. Walsh;C. Liston;Joshua Levitz;R. Garippa;Shuibing Chen;G. Ciceri;L. Studer
人类多能干细胞（hPSC）衍生的神经元的成熟模仿了人类大脑发育的漫长时间，延长了几个月甚至几年，达到成人的功能。长时间的体外成熟对干细胞在神经系统疾病建模和治疗中的应用提出了重大挑战。我们设计了一种基于hpsc衍生皮质神经元形态学和功能读数的高含量成像分析，以揭示潜在的通路并识别能够加速神经元成熟的化学物质。通过对2688种生物活性药物的研究，我们发现了多种驱动神经元成熟的化合物，包括LSD1和DOT1L的抑制剂以及钙依赖性转录的激活剂。GSK-2879552、EPZ-5676、NMDA和Bay K 8644这4个因子（我们统称为GENtoniK）的混合物在所有测试中触发成熟，包括突触密度、电生理和转录组学的测量。值得注意的是，GENtoniK在促进3D皮质类器官和脊髓运动神经元的神经元成熟方面同样有效，并改善非神经谱系（如黑素细胞和胰腺β细胞）的细胞成熟方面。这些结果表明，多种hpsc衍生的细胞类型的成熟可以通过简单的药物干预来增强，并表明控制人类成熟时间的一些机制是跨谱系共享的。
The maturation of human pluripotent stem cell (hPSC)-derived neurons mimics the protracted timing of human brain development, extending over months and years to reach adult-like function. Prolonged in vitro maturation presents a major challenge to stem cell-based applications in modeling and treating neurological disease. We designed a high-content imaging assay based on morphological and functional readouts in hPSC-derived cortical neurons to reveal underlying pathways and to identify chemicals capable of accelerating neuronal maturation. Probing a library of 2688 bioactive drugs, we identified multiple compounds that drive neuronal maturation including inhibitors of LSD1 and DOT1L and activators of calcium-dependent transcription. A cocktail of 4 factors GSK-2879552, EPZ-5676, NMDA and Bay K 8644, which we collectively termed GENtoniK, triggered maturation across all assays tested including measures of synaptic density, electrophysiology and transcriptomics. Remarkably, GENtoniK was similarly effective in enhancing neuronal maturation in 3D cortical organoids and in spinal motoneurons, and improved aspects of cell maturation in non-neural lineages such as melanocytes and pancreatic beta cells. These results demonstrate that the maturation of multiple hPSC-derived cell types can be enhanced by simple pharmacological intervention and suggests that some of the mechanisms controlling the timing of human maturation are shared across lineages.
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通讯作者：
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