Tryptophan Hydroxylase-2-Mediated Serotonin Biosynthesis Suppresses Cell Reprogramming into Pluripotent State

Abstract

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.

Metabolic control of induced pluripotency

“…The biosynthesis of the neurotransmitter serotonin by a rate-limiting enzyme, tryptophan hydroxylase-2 (TPH2), is also involved in the regulation of cell reprogramming. Removing TPH2 function during the entire reprogramming process majorly enhances the efficiency of iPSC generation, while TPH2 induction suppresses the process, indicating the importance of tryptophan pool or serotonin signaling in pluripotency acquisition ( Sinenko et al, 2023 ). The latter possibility is supported by the observed activity of serotonin in the positive regulation of mitochondrial functions and biogenesis ( Fanibunda et al, 2019 ; Rao et al, 2023 ).…”

Tryptophan in Nutrition and Health 2.0

“…The neuroprotective tryptophan derivative melatonin can determine the brain–heart crosstalk [ 6 ]. New data suggest a modulatory role of serotonin biosynthesis in the reprogramming of somatic cells to a pluripotent state [ 7 ]. Activation of the kynurenine and indolamine pathways of the tryptophan metabolism is linked to a plethora of neuropsychiatric disorders [ 8 ].…”

“…The tryptophan metabolism can be influenced to prevent and reverse premature aging characterized by inflammation and oxidative stress [ 1 , 2 ]. Targeting tryptophan and the tryptophan pathway can enable novel strategies for diagnosis, prevention, treatment, and rehabilitation to improve, maintain, and restore health [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ].…”