Maternal erythrocyte ENT1–mediated AMPK activation counteracts placental hypoxia and supports fetal growth

Sayama, Seisuke; Song, Anren; Brown, Barbara I.; Couturier, Jacob; Cai, Xiaoli; Xu, Ping; Chen, Chang‐Han; Zheng, Yaqiu; Iriyama, Takayuki; Sibai, Baha M.; Longo, Monica; Kellems, Rodney E.; D’Alessandro, Angelo; Xia, Yang

doi:10.1172/jci.insight.130205

Cited by 20 publications

(19 citation statements)

References 31 publications

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“…We believe that this study is the rst to report the potential role of miR-210-5p in the pathogenesis of FGR. Dysregulated expression of miR-210-5p under hypoxic conditions further supports our study, as hypoxia is frequently associated with FGR [12,13].…”

Section: Discussionsupporting

confidence: 88%

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Circular RNA hsa_circ_0081343 promotes trophoblast cell migration and invasion and inhibits trophoblast apoptosis by regulating miR-210-5p/DLX3 axis

Xie

Wang

Luo

et al. 2021

Preprint

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Background: Various circular RNAs (circRNAs) are dysregulated in the placenta of fetal growth restriction fetuses, but their role and regulatory mechanisms have not been fully elucidated. Herein, we aimed to elucidate the role of hsa_circ_0081343 in regulating the migration, invasion, and apoptosis in the human extravillous trophoblast HTR-8 cells.Methods: circRNA and miRNA levels were examined using quantitative real-time PCR (RT-PCR). Overexpression plasmid constructs and siRNA were used to overexpress and knockdown hsa_circ_0081343, respectively. Transwell assay and flow cytometry analysis were performed to evaluate the effect of hsa_circ_0081343 or miR-210-5p on migration, invasion, and apoptosis. Protein levels were analyzed using western blot. Dual luciferase activity assay and anti-AGO2 RNA immunoprecipitation (RIP) assays were performed to identify the relationship between miR-210-5p and hsa_circ_0081343.Results: Hsa_circ_0081343 expression was significantly downregulated in 37 FGR placental tissues as compared to healthy placental control tissues. Hsa_circ_0081343 overexpression possibly inhibits apoptosis by downregulating the expression of cleaved caspase 3 and caspase 9 and alleviates the migration and invasion of HTR-8 cells by inducing the expression of MMP2 and MMP9. The dual luciferase activity and anti-AGO2 RIP assay results showed that hsa_circ_0081343 binds to miR-210-5p. miR-210-5p overexpression eliminated the effect of hsa_circ_0081343 overexpression in HTR-8 cells. Finally, DLX3 was identified as a direct target of miR-210-5p. Conclusions: Hsa_circ_0081343 regulates the migration, invasion, and apoptosis of HTR-8 cells via the hsa-miR-210-5p/DLX3 axis. Thus, hsa_circ_0081343 plays a key role in the etiology and pathogenesis of FGR implicating its importance as a novel candidate for targeted FGR therapy.

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Section: Discussionsupporting

confidence: 88%

“…A review of literature revealed that miR-210-5p is a hypoxia-regulated miRNA [12]. Moreover, hypoxia is frequently associated with FGR [13]. Consequently, we focused on the relationship between miR-210-5p and hsa_circ_0081343.…”

Section: Hsa_circ_0081343 Promotes Migration and Invasion; And Inhibimentioning

confidence: 99%

Circular RNA hsa_circ_0081343 promotes trophoblast cell migration and invasion and inhibits trophoblast apoptosis by regulating miR-210-5p/DLX3 axis

Xie

Wang

Luo

et al. 2021

Preprint

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“…Since Adk catalyzes adenosine phosphorylation to yield AMP, and erythroid Slc29a1 loss decreases AMP levels and AMPK phosphorylation in mature erythrocytes [ 48 ], we asked if Slc29a1 downregulation decreases intracellular AMP in primary erythroblasts cultured ex vivo under conditions that promote erythroid cell expansion and differentiation. We isolated HSPCs from murine E14.5 fetal livers, infected them with two different shRNAs targeting Slc29a1 or luciferase , and quantified AMP and ATP levels after sorting GFP-positive erythroblasts.…”

Section: Resultsmentioning

confidence: 99%

GATA factor-regulated solute carrier ensemble reveals a nucleoside transporter-dependent differentiation mechanism

Zwifelhofer

Cai²,

Liao

et al. 2020

PLoS Genet

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Developmental-regulatory networks often include large gene families encoding mechanistically-related proteins like G-protein-coupled receptors, zinc finger transcription factors and solute carrier (SLC) transporters. In principle, a common mechanism may confer expression of multiple members integral to a developmental process, or diverse mechanisms may be deployed. Using genetic complementation and enhancer-mutant systems, we analyzed the 456 member SLC family that establishes the small molecule constitution of cells. This analysis identified SLC gene cohorts regulated by GATA1 and/or GATA2 during erythroid differentiation. As >50 SLC genes shared GATA factor regulation, a common mechanism established multiple members of this family. These genes included Slc29a1 encoding an equilibrative nucleoside transporter (Slc29a1/ENT1) that utilizes adenosine as a preferred substrate. Slc29a1 promoted erythroblast survival and differentiation ex vivo. Targeted ablation of murine Slc29a1 in erythroblasts attenuated erythropoiesis and erythrocyte regeneration in response to acute anemia. Our results reveal a GATA factor-regulated SLC ensemble, with a nucleoside transporter component that promotes erythropoiesis and prevents anemia, and establish a mechanistic link between GATA factor and adenosine mechanisms. We propose that integration of the GATA factor-adenosine circuit with other components of the GATA factor-regulated SLC ensemble establishes the small molecule repertoire required for progenitor cells to efficiently generate erythrocytes.

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“…The copyright holder for this this version posted October 26, 2020. ; https://doi.org/10.1101/2020.10.25.334201 doi: bioRxiv preprint adenosine homeostasis. A recent study demonstrated that genetic deletion of ENT1 reduces adenosine uptake and impacts AMPK activity (Sayama et al, 2020). In the early stages of Alzheimer's Disease, the level of adenosine is reduced in the frontal cortex but is enhanced in the parietal and temporal cortices.…”

Section: Discussionmentioning

confidence: 99%

“…Because adenosine homeostasis has been implicated in the regulation of AMPK activation (Pastor-Anglada et al, 2007;Medina-Pulido et al, 2013;Sayama et al, 2020), and since AMPK directly phosphorylates Tau (Domise et al, 2016), we next evaluated the activation/phosphorylation of AMPK (Thr 172 , designated pAMPK) and…”

Section: Tau22 Micementioning

confidence: 99%

A novel equilibrative nucleoside transporter 1 inhibitor alleviates Tau-mediated neurodegeneration

Chang

Chuang

et al. 2020

Preprint

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Tau hyperphosphorylation favors the formation of neurofibrillary tangles and triggers the gradual loss of neuronal functions in tauopathies, including Alzheimer's disease. Herein, we demonstrated that chronic treatment with an inhibitor (J4) of equilibrative nucleoside transporter 1 (ENT1), which plays a critical role in controlling adenosine homeostasis and purine metabolism in the brain, exerted beneficial effects in a mouse model of tauopathy (Thy-Tau22, Tau22). Chronic treatment with J4 improved spatial memory deficits, mitochondrial dysfunction, synaptic plasticity impairment, and gliosis. Immunofluorescence assays showed that J4 not only reduced Tau hyperphosphorylation but also normalized the reduction in mitochondrial mass and suppressed the abnormal activation of AMP-activated protein kinase (AMPK), a pathogenic feature that is also observed in the brains of patients with tauopathies. Given that AMPK is an important energy sensor, our findings suggest that energy dysfunction is associated with tauopathy and that J4 may exert its protective effect by improving energy homeostasis. Bulk RNA-seq analysis revealed that J4 also mitigated immune signature associated with Tau pathology including C1q upregulation and A1 astrocyte markers. Collectively, our findings suggest that identifying strategies for normalizing energy and neuroimmune dysfunctions in tauopathies through adenosinergic signaling modulation may pave the way for the development of treatments for Alzheimer's disease.

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Maternal erythrocyte ENT1–mediated AMPK activation counteracts placental hypoxia and supports fetal growth

Cited by 20 publications

References 31 publications

Circular RNA hsa_circ_0081343 promotes trophoblast cell migration and invasion and inhibits trophoblast apoptosis by regulating miR-210-5p/DLX3 axis

Circular RNA hsa_circ_0081343 promotes trophoblast cell migration and invasion and inhibits trophoblast apoptosis by regulating miR-210-5p/DLX3 axis

GATA factor-regulated solute carrier ensemble reveals a nucleoside transporter-dependent differentiation mechanism

A novel equilibrative nucleoside transporter 1 inhibitor alleviates Tau-mediated neurodegeneration

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