Institute of Translational Biomedicine, Saint-Petersburg State University, 199034 Saint-Petersburg, Russia.
Almazov National Medical Research Centre, 197341 Saint-Petersburg, Russia.
Int J Mol Sci. 2023 Jan 11;24(2):1429. doi: 10.3390/ijms24021429.
Elaboration of protocols for differentiation of human pluripotent stem cells to dopamine neurons is an important issue for development of cell replacement therapy for Parkinson's disease. A number of protocols have been already developed; however, their efficiency and specificity still can be improved. Investigating the role of signaling cascades, important for neurogenesis, can help to solve this problem and to provide a deeper understanding of their role in neuronal development. Notch signaling plays an essential role in development and maintenance of the central nervous system after birth. In our study, we analyzed the effect of Notch activation and inhibition at the early stages of differentiation of human induced pluripotent stem cells to dopaminergic neurons. We found that, during the first seven days of differentiation, the cells were not sensitive to the Notch inhibition. On the contrary, activation of Notch signaling during the same time period led to significant changes and was associated with an increase in expression of genes, specific for caudal parts of the brain, a decrease of expression of genes, specific for forebrain, as well as a decrease of expression of genes, important for the formation of axons and dendrites and microtubule stabilizing proteins.
制定人类多能干细胞向多巴胺神经元分化的方案是开发帕金森病细胞替代治疗的重要问题。已经开发了许多方案；然而，它们的效率和特异性仍然可以提高。研究对神经发生很重要的信号级联的作用可以帮助解决这个问题，并提供对其在神经元发育中的作用的更深入了解。Notch 信号在出生后中枢神经系统的发育和维持中起着至关重要的作用。在我们的研究中，我们分析了 Notch 激活和抑制对人诱导多能干细胞向多巴胺能神经元分化早期的影响。我们发现，在分化的头七天，细胞对 Notch 抑制不敏感。相反，在同一时期激活 Notch 信号会导致显著变化，并与大脑尾部特异性基因的表达增加、前脑特异性基因的表达减少以及对轴突和树突形成和微管稳定蛋白很重要的基因的表达减少有关。
