Trophoblast Differentiation Affects Crucial Nutritive Functions of Placental Membrane Transporters

Karahoda, Rona; Zaugg, Jonas; Fuenzalida, Bárbara; Kallol, Sampada; Moser-Haessig, Ruedi; Štaud, František; Albrecht, Christiane

doi:10.3389/fcell.2022.820286

Cited by 13 publications

(12 citation statements)

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“…Previous studies have shown that the trophoblast differentiation process is associated with simultaneous induction and repression of numerous genes that encode functionally related proteins [ 38 , 39 ]. We have also recently found that several placental membrane proteins responsible for the transport of nutrients and xenobiotics are differentially expressed in the CTB and STB stages [ 33 ]. Here, we show that the expression of key monoamine transporters (SERT, NET, and DAT) is significantly altered during, and after, placental cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Expression levels of the following genes were estimated: NET/SLC6A2 (Hs00426573_ m1), DAT/SLC6A3 (Hs00997374_m1), SERT/SLC6A4 (Hs00984349_m1), OCT3/SLC22A3 (Hs01009571_m1), and hCG/CGB3 (Hs00361224_gH). For this, transcripts of the genes were amplified in triplicate, using thermal programs recommended by the manufacturer, and quantified by the ΔΔCt method with YWHAZ Vachalova et al Reproductive Biology and Endocrinology (2022) 20:112 (Hs01122445_g1) and B2M (Hs00187842_m1) as reference genes, as previously described [33].…”

Section: Reverse Transcription and Gene Expression Analysismentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Reverse Transcription and Gene Expression Analysismentioning

confidence: 99%

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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“…Various ABC transporters have been identified in the placenta and their localization and function at the maternal–fetal interface across gestation has been studied [ 35 ]. It is well-known that alterations in the expression of these transporters during different stages of gestation or due to ABC transporter modulators can lead to changes in the transfer of substrates to and from the fetus [ 9 , 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Palmitic Acid Impedes Extravillous Trophoblast Activity by Increasing MRP1 Expression and Function

Ashar

Teng²,

Wurpel³

et al. 2022

Biomolecules

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Normal function of placental extravillous trophoblasts (EVTs), which are responsible for uteroplacental vascular remodeling, is critical for adequate delivery of oxygen and nutrients to the developing fetus and normal fetal programming. Proliferation and invasion of spiral arteries by EVTs depends upon adequate levels of folate. Multidrug resistance-associated protein 1 (MRP1), which is an efflux transporter, is known to remove folate from these cells. We hypothesized that palmitic acid increases MRP1-mediated folate removal from EVTs, thereby interfering with EVTs’ role in early placental vascular remodeling. HTR-8/SVneo and Swan-71 cells, first trimester human EVTs, were grown in the absence or presence of 0.5 mM and 0.7 mM palmitic acid, respectively, for 72 h. Palmitic acid increased ABCC1 gene expression and MRP1 protein expression in both cell lines. The rate of folate efflux from the cells into the media increased with a decrease in migration and invasion functions in the cultured cells. Treatment with N-acetylcysteine (NAC) prevented the palmitic acid-mediated upregulation of MRP1 and restored invasion and migration in the EVTs. Finally, in an ABCC1 knockout subline of Swan-71 cells, there was a significant increase in invasion and migration functions. The novel finding in this study that palmitic acid increases MRP1-mediated folate efflux provides a missing link that helps to explain how maternal consumption of saturated fatty acids compromises the in utero environment.

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“…Various ABC transporters have been identified in the placenta and their localization and function at the maternal-fetal interface across gestation has been studied [36]. It is well known that alterations in the expression of these transporters during different stages of gestation or due to ABC transporter modulators can lead to changes in the transfer of substrates to and from the fetus [9,37,38].…”

Section: Discussionmentioning

confidence: 99%

Palmitic Acid Impedes Extravillous Trophoblast Activity by Increasing MRP1 Expression and Function

Ashar¹,

Teng²,

Wurpel³

et al. 2022

Preprint

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Normal function of placental extravillous trophoblasts (EVTs), which are responsible for uteroplacental vascular remodeling, is critical for adequate delivery of oxygen and nutrients to the developing fetus and normal fetal programming. Proliferation and invasion of spiral arteries by EVTs depends upon adequate levels of folate. Multidrug resistance-associated protein 1 (MRP1), which is an efflux transporter, is known to remove folate from these cells. We hypothesized that palmitic acid increases MRP1-mediated folate removal from EVTs, thereby interfering with EVTs’ role in early placental vascular remodeling. HTR-8/SVneo and Swan-71 cells, first trimester human EVTs, were grown in the absence or presence of 0.5 mM and 0.7 mM palmitic acid, respectively, for 72 h. Palmitic acid increased ABCC1 gene expression and MRP1 protein expression in both cell lines. The rate of folate efflux from the cells into the media increased with a decrease in migration and invasion functions in the cultured cells. Treatment with N-acetyl cysteine (NAC) prevented the palmitic acid mediated upregulation of MRP1 and restored invasion and migration in the EVTs. Finally, in an ABCC1 knockout subline of Swan-71 cells, there was a significant increase in invasion and migration functions. The novel finding in this study that palmitic acid increases MRP1-mediated folate efflux provides a missing link that helps to explain how maternal consumption of saturated fatty acids compromises the in-utero environment.

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Trophoblast Differentiation Affects Crucial Nutritive Functions of Placental Membrane Transporters

Cited by 13 publications

References 71 publications

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

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

RETRACTED: Palmitic Acid Impedes Extravillous Trophoblast Activity by Increasing MRP1 Expression and Function

Palmitic Acid Impedes Extravillous Trophoblast Activity by Increasing MRP1 Expression and Function

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