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

July 20, 2023

Sergey A. Sinenko, Andrey A. Kuzmin, Elena V. Skvortsova, Sergey V. Ponomartsev, Evgeniya V. Efimova, Michael Bader, Natalia Alenina, Alexey N. Tomilin

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

Journal: International Journal of Molecular Sciences