How trophoblasts fuse: an in-depth look into placental syncytiotrophoblast formation

Renaud, Stephen J.; Jeyarajah, Mariyan

doi:10.1007/s00018-022-04475-z

Cited by 35 publications

(33 citation statements)

References 251 publications

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“…The BeWo cell line is an established model system where forskolin, an adenylase cyclase activator upstream of protein kinase A, induces both biochemical and morphologic syncytialization (Orendi et al, 2011;Rothbauer et al, 2017). These differentiation parameters are detected through production of human chorionic gonadotrophin (HCG) and coordinated changes in gene transcription along with fusion of cell membranes resulting in morphologic syncytia (Costa, 2016;Renaud and Jeyarajah, 2022).…”

Section: Resultsmentioning

confidence: 99%

Metformin impairs trophoblast metabolism and differentiation in dose dependent manner

Nashif

Mahr

Jena

et al. 2023

Preprint

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Metformin is a widely prescribed medication whose mechanism of action in not completely defined and whose role in gestational diabetes management remains controversial. In addition to increasing risks of fetal growth abnormalities and preeclampsia, gestational diabetes is associated with abnormalities in placental development including impairments in trophoblast differentiation. Given that metformin impacts cellular differentiation events in other systems, we assessed metformin's impact on trophoblast metabolism and differentiation. Using established cell culture models of trophoblast differentiation, oxygen consumption rates and relative metabolite abundance were determined following 200 μM (near-physiologic) and 2000 μM (supra-physiologic) metformin treatment using Seahorse and mass-spectrometry approaches. While no differences in oxygen consumption rates or relative metabolite abundance was detected between vehicle and 200 μM metformin treated cells, 2000 μM metformin impaired oxidative metabolism and increased abundance of lactate and TCA cycle intermediates, α-ketoglutarate, succinate, and malate. Examining differentiation, treatment with 2000 μM, but not 200 μM metformin, impaired HCG production and expression of multiple trophoblast differentiation markers. Overall, this work suggests that supra-physiologic concentrations of metformin impairs trophoblast metabolism and differentiation whereas physiologic concentrations of metformin do not strongly impact these processes.

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Section: Resultsmentioning

confidence: 99%

Metformin impairs trophoblast metabolism and differentiation in dose dependent manner

Nashif

Mahr

Jena

et al. 2023

Preprint

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“…Trophoblast differentiation alters metabolite abundance, energy charge, and glucose utilization Throughout gestation, cytotrophoblasts fuse to form and renew syncytiotrophoblasts. 4,5,8 Prior work demonstrates cytotrophoblasts and syncytiotrophoblasts differ in their oxygen consumption rate. 17,18 However, it is unclear how differentiation impacts relative abundance of key glycolytic and TCA cycle intermediates and energy metabolites.…”

Section: Resultsmentioning

confidence: 99%

“…2,3 Throughout pregnancy, cytotrophoblasts divide and fuse to maintain this syncytial layer through tightly regulated processes requiring the coordination of signaling, transcriptional and cellular fusion machinery. 4,5 Abnormalities in syncytialization are associated with pregnancy complications including fetal growth abnormalities, preeclampsia, gestational diabetes, and stillbirth. 6,7 During the process of trophoblast differentiation, coordinated transcriptional reprogramming increases expression of gene products involved in syncytia formation and function including HCG (CGA and CGB), fusion proteins Syncytin 1 and Syncytin 2 (ERVW and ERVFRD), and transcription factors including those encoded by GCM1, OVOL1, and GATA2.…”

Section: Introductionmentioning

confidence: 99%

“…6,7 During the process of trophoblast differentiation, coordinated transcriptional reprogramming increases expression of gene products involved in syncytia formation and function including HCG (CGA and CGB), fusion proteins Syncytin 1 and Syncytin 2 (ERVW and ERVFRD), and transcription factors including those encoded by GCM1, OVOL1, and GATA2. 4,5,[8][9][10] In addition, gene products required for cytotrophoblast lineages including the transcription factors, TEAD4 and TP63 are downregulated. Epigenetic modifications, including histone acetylation, play a critical role in this process.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation

Mahr

Jena

Nashif

et al. 2023

Preprint

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Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established cell culture model of trophoblast differentiation. Trophoblast differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.

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Somatic Cell Fusion in Host Defense and Adaptation

Platt,

Cascalho

2023

Results and Problems in Cell Differentiation

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How trophoblasts fuse: an in-depth look into placental syncytiotrophoblast formation

Cited by 35 publications

References 251 publications

Metformin impairs trophoblast metabolism and differentiation in dose dependent manner

Metformin impairs trophoblast metabolism and differentiation in dose dependent manner

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation

Somatic Cell Fusion in Host Defense and Adaptation

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