| 其他摘要 | Long-term exposure to microgravity has not only affected the cardiovascular system, skeletal muscle system, and immune system of astronauts but changed the structure of the nervous system and cognitive function. Human Neural Progenitor Cells (hNPCs) are the basis of the central nervous system involved in the development of the nervous system and the occurrence of neuropsychiatric diseases. Therefore, the study of the biological effects of simulated microgravity on hNPCs differentiation and analysis of the molecular mechanism of simulated microgravity on neuronal development, so as provide an effective way to explore the mechanism of microgravity causing neurological disorders.
In this study, the forebrain hNPCs derived from human induced pluripotent stem cells (hiPSCs) were differentiated into cortical neurons under simulated microgravity, to mimic the development of the embryonic neocortex and investigate the changes of neuronal types, morphology, synaptic proteins, and functional activity. Effects of microgravity on specific neuronal clusters and gene expression were analyzed by single-cell transcriptome sequencing to explore the molecular mechanism of simulated microgravity on human neural development.
Morphological staining showed that simulated microgravity increased the morphological complexity, decreased the expression of BRN2, a marker of the superficial cortex, and increased the expression of Synapsinlin differentiated neurons. Further analysis showed that the expression of inhibitory neuron marker VGAT1 increased, while the expression of excitatory neuron marker VGLUTI had no effect, suggesting that simulated microgravity may promote the development of inhibitory neurons. Calcium imaging analysis showed that simulated microgravity enhanced the activity of neurons. Single-cell transcriptome analysis showed that the proportion of neurons was increased compared with neural progenitor cells, and the genes related to neural differentiation were upregulated under simulated microgravity. Besides, the increased expression of genes related to the development of neurons, synaptic plasticity (MEF2C, PSD3), and neurotrophic factor pathway (VGF, NTRK2), which may be the potential molecular mechanism of microgravity on neural differentiation.
In conclusion, simulated microgravity promoted the differentiation of hiPSCs-derived hNPCs towards neurons, especially inhibitory neurons. In addition, simulated microgravity increased the expression of synaptic proteins and improved the functional activity of neurons. The significantly differentially expressed genes such as MEF2C, PSD3, and VGF may be the key molecules that simulated microgravity to regulate the differentiation of neural progenitor cells and synaptic plasticity. Understanding the biological effect of simulated microgravity on neural progenitor cell differentiation and its mechanism will provide new ideas for stem cell therapy of neuropsychiatric diseases. |
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