Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064 St. Petersburg, Russia.
Institute of Translational Biomedicine, St-Petersburg State University, 7-9 Universitetskaya Emb, 199034 St. Petersburg, Russia.
Int J Mol Sci. 2023 Mar 2;24(5):4862. doi: 10.3390/ijms24054862.
The monoamine neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has important functions both in the neural system and during embryonic development in mammals. In this study, we set out to investigate whether and how endogenous serotonin affects reprogramming to pluripotency. As serotonin is synthesized from tryptophan by the rate limiting enzymes tryptophan hydroxylase-1 and -2 (TPH1 and TPH2), we have assessed the reprogramming of TPH1- and/or TPH2-deficient mouse embryonic fibroblasts (MEFs) to induced pluripotent stem cells (iPSCs). The reprogramming of the double mutant MEFs showed a dramatic increase in the efficiency of iPSC generation. In contrast, ectopic expression of TPH2 alone or in conjunction with TPH1 reverted the rate of reprogramming of the double mutant MEFs to the wild-type level and besides, TPH2 overexpression significantly suppressed reprogramming of wild-type MEFs. Our data thus suggest a negative role of serotonin biosynthesis in the reprogramming of somatic cells to a pluripotent state.
单胺神经递质 5-羟色胺（5-HT）在哺乳动物的神经系统和胚胎发育中具有重要功能。在这项研究中，我们着手研究内源性 5-羟色胺是否以及如何影响重编程为多能性。由于 5-羟色胺是由色氨酸通过限速酶色氨酸羟化酶-1 和 -2（TPH1 和 TPH2）合成的，因此我们评估了 TPH1 和/或 TPH2 缺陷型小鼠胚胎成纤维细胞（MEFs）向诱导多能干细胞（iPSCs）的重编程。双突变 MEFs 的重编程显示出 iPSC 生成效率的显著提高。相比之下，TPH2 的异位表达单独或与 TPH1 一起恢复了双突变 MEFs 的重编程速率至野生型水平，此外，TPH2 过表达显著抑制了野生型 MEFs 的重编程。因此，我们的数据表明 5-羟色胺生物合成在体细胞重编程为多能状态中起负作用。
