Differential Serotonin Uptake Mechanisms at the Human Maternal–Fetal Interface

Baković, Petra; Kesić, Maja; Perić, Maja; Bečeheli, Ivona; Horvatiček, Marina; George, Meekha; Čičin‐Šain, Lipa; Desoyé, Gernot; Wadsack, Christian; Panzenboeck, Ute; Štefulj, Jasminka

doi:10.3390/ijms22157807

Cited by 16 publications

(16 citation statements)

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“…In this study we further found that, at pharmacologically relevant drug concentrations, a wide range of selective serotonin reuptake inhibitors impair serotonin cellular accumulation in both PHT and BeWo cells. Similar observations in PHT cells have also been recently reported, with half-maximal inhibitory concentrations in the 2-11 nM range [56], highlighting these drugs' potentially negative effects on cellular serotonin processing. However, the extent of serotonin uptake inhibition by these drugs differs between PHT and BeWo cells, probably due to the lack of OCT3 (which is also sensitive to selective serotonin uptake inhibitors [57]).…”

Section: Discussionsupporting

confidence: 87%

Functional reorganization of monoamine transport systems during villous trophoblast differentiation: evidence of distinct differences between primary human trophoblasts and BeWo cells

Váchalová

Karahoda

Ottaviani

et al. 2022

Reprod Biol Endocrinol

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Background Three primary monoamines—serotonin, norepinephrine, and dopamine—play major roles in the placenta-fetal brain axis. Analogously to the brain, the placenta has transport mechanisms that actively take up these monoamines into trophoblast cells. These transporters are known to play important roles in the differentiated syncytiotrophoblast layer, but their status and activities in the undifferentiated, progenitor cytotrophoblast cells are not well understood. Thus, we have explored the cellular handling and regulation of monoamine transporters during the phenotypic transitioning of cytotrophoblasts along the villous pathway. Methods Experiments were conducted with two cellular models of syncytium development: primary trophoblast cells isolated from the human term placenta (PHT), and the choriocarcinoma-derived BeWo cell line. The gene and protein expression of membrane transporters for serotonin (SERT), norepinephrine (NET), dopamine (DAT), and organic cation transporter 3 (OCT3) was determined by quantitative PCR and Western blot analysis, respectively. Subsequently, the effect of trophoblast differentiation on transporter activity was analyzed by monoamine uptake into cells. Results We present multiple lines of evidence of changes in the transcriptional and functional regulation of monoamine transporters associated with trophoblast differentiation. These include enhancement of SERT and DAT gene and protein expression in BeWo cells. On the other hand, in PHT cells we report negative modulation of SERT, NET, and OCT3 protein expression. We show that OCT3 is the dominant monoamine transporter in PHT cells, and its main functional impact is on serotonin uptake, while passive transport strongly contributes to norepinephrine and dopamine uptake. Further, we show that a wide range of selective serotonin reuptake inhibitors affect serotonin cellular accumulation, at pharmacologically relevant drug concentrations, via their action on both OCT3 and SERT. Finally, we demonstrate that BeWo cells do not well reflect the molecular mechanisms and properties of healthy human trophoblast cells. Conclusions Collectively, our findings provide insights into the regulation of monoamine transport during trophoblast differentiation and present important considerations regarding appropriate in vitro models for studying monoamine regulation in the placenta.

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Section: Discussionsupporting

confidence: 87%

Functional reorganization of monoamine transport systems during villous trophoblast differentiation: evidence of distinct differences between primary human trophoblasts and BeWo cells

Váchalová

Karahoda

Ottaviani

et al. 2022

Reprod Biol Endocrinol

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“…On the other hand, recent study found that SERT mRNA levels were upregulated during spontaneous syncytialization of human primary trophoblasts, but SERT protein and activity levels were downregulated by syncytialization ( 95 ). Low levels of SERT mRNA and SERT protein were also detected in feto-placental endothelial cells ( 80 , 82 , 89 ), but functional analysis did not support significant SERT activity in these cells ( 89 ).…”

Section: Serotonin System and Its Components In The Human Placentamentioning

confidence: 93%

“…Serotonin catabolizing isoenzyme MAOA is abundant in the human placenta throughout pregnancy, as demonstrated by IHC ( 82 ) and enzyme activity studies ( 69 ). Known sites of MAOA expression in human placenta appear to be syncytiotrophoblast ( 29 , 72 , 82 , 84 ), cytotrophoblasts ( 72 , 87 , 88 ) and feto-placental endothelial cells ( 89 ). Single cell transcriptomic data show that syncytiotrophoblast as compared with cytotrophoblasts contain much higher levels of MAOA mRNA (about 10-fold higher in the first trimester, and about 2-fold higher at term) ( 87 , 88 ).…”

Section: Serotonin System and Its Components In The Human Placentamentioning

confidence: 99%

“…Human placenta expresses several plasma membrane transporters for serotonin. Activity of the high-affinity SERT has been shown in plasma membrane vesicles ( 70 , 94 ) and primary trophoblasts ( 89 ) isolated from human term placenta. SERT mRNA levels were lower in term compared to first trimester placentas, while the opposite was found for SERT protein levels ( 69 ).…”

Section: Serotonin System and Its Components In The Human Placentamentioning

confidence: 99%

“…Low-affinity, polyspecific transporters OCT1 and OCT2 have been reported to be absent ( 77 ) or expressed at very low levels ( 74 – 76 , 78 , 89 ) in human first trimester and term placentas. This is consistent with the absence of their mRNAs in single cell transcriptome analyses ( 87 , 88 ).…”

Section: Serotonin System and Its Components In The Human Placentamentioning

confidence: 99%

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Serotonin system in the human placenta – the knowns and unknowns

et al. 2022

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The biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT) is a chemical messenger widely distributed in the brain and various other organs. Its homeostasis is maintained by the coordinated activity of a variety of proteins, including enzymes of serotonin metabolism, transmembrane transporters of serotonin, and serotonin receptors. The serotonin system has been identified also in the placenta in rodent models as a key component of placental physiology. However, serotonin pathways in the human placenta are far from well understood. Their alterations may have long-lasting consequences for the fetus that can manifest later in life. In this review, we summarize information on the location of the components of the serotonin system in the human placenta, their regulation, function, and alterations in pathological pregnancies. We highlight current controversies and discuss important topics for future research.

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