Differential 5'-tRNA Fragment Expression in Circulating Preeclampsia Syncytiotrophoblast Vesicles Drives Macrophage Inflammation

Overview

Journal Hypertension

Date 2024 Feb 16

PMID 38362745

Authors

William R Cooke

Peiyong Jiang

Lu Ji

Jinyue Bai

Gabriel Davis Jones

Y M Dennis Lo

Christopher Redman

Manu Vatish

Affiliations

Soon will be listed here.

Abstract

Background: The relationship between placental pathology and the maternal syndrome of preeclampsia is incompletely characterized. Mismatch between placental nutrient supply and fetal demands induces stress in the syncytiotrophoblast, the layer of placenta in direct contact with maternal blood. Such stress alters the content and increases the release of syncytiotrophoblast extracellular vesicles (STB-EVs) into the maternal circulation. We have previously shown 5'-tRNA fragments (5'-tRFs) constitute the majority of small RNA in STB-EVs in healthy pregnancy. 5'-tRFs are produced in response to stress. We hypothesized STB-EV 5'-tRF release might change in preeclampsia.

Methods: We perfused placentas from 8 women with early-onset preeclampsia and 6 controls, comparing small RNA expression in STB-EVs. We used membrane-affinity columns to isolate maternal plasma vesicles and investigate placental 5'-tRFs in vivo. We quantified 5'-tRFs from circulating STB-EVs using a placental alkaline phosphatase immunoassay. 5'-tRFs and scrambled RNA controls were added to monocyte, macrophage and endothelial cells in culture to investigate transcriptional responses.

Results: 5'-tRFs constitute the majority of small RNA in STB-EVs from both preeclampsia and normal pregnancies. More than 900 small RNA fragments are differentially expressed in preeclampsia STB-EVs. Preeclampsia-dysregulated 5'-tRFs are detectable in maternal plasma, where we identified a placentally derived load. 5'-tRF-Glu-CTC, the most abundant preeclampsia-upregulated 5'-tRF in perfusion STB-EVs, is also increased in preeclampsia STB-EVs from maternal plasma. 5'-tRF-Glu-CTC induced inflammation in macrophages but not monocytes. The conditioned media from 5'-tRF-Glu-CTC-activated macrophages reduced eNOS (endothelial NO synthase) expression in endothelial cells.

Conclusions: Increased release of syncytiotrophoblast-derived vesicle-bound 5'-tRF-Glu-CTC contributes to preeclampsia pathophysiology.

Citing Articles

Comprehensive profiling of small RNAs and their changes and linkages to mRNAs in schizophrenia and bipolar disorder.

Nersisyan S, Loher P, Nazeraj I, Shao Z, Fullard J, Voloudakis G bioRxiv. 2025; .

PMID: 39763727 PMC: 11703252. DOI: 10.1101/2024.12.24.630254.

Extracellular Vesicles as Biomarkers of Pregnancy Complications.

Popova A, Vashukova E, Illarionov R, Maltseva A, Pachuliia O, Postnikova T Int J Mol Sci. 2024; 25(22).

PMID: 39596014 PMC: 11594130. DOI: 10.3390/ijms252211944.

Small and Long Non-Coding RNA Analysis for Human Trophoblast-Derived Extracellular Vesicles and Their Effect on the Transcriptome Profile of Human Neural Progenitor Cells.

Kinkade J, Singh P, Verma M, Khan T, Ezashi T, Bivens N Cells. 2024; 13(22).

PMID: 39594615 PMC: 11593255. DOI: 10.3390/cells13221867.

Placenta Extracellular Vesicles: Messengers Connecting Maternal and Fetal Systems.

Rosenfeld C Biomolecules. 2024; 14(8).

PMID: 39199382 PMC: 11352387. DOI: 10.3390/biom14080995.

MIR193BHG inhibits the proliferation, migration and invasion of trophoblasts by upregulating p53.

Wang P, Chen Y, Yang S, Gao J, Zhang Z, Li H Exp Ther Med. 2024; 28(2):320.

PMID: 38939173 PMC: 11208764. DOI: 10.3892/etm.2024.12609.

References

Meng L, Jiang L, Chen J, Ren H, Gao Z, Wu F . Transfer RNA-derived fragment tRF-28-QSZ34KRQ590K in plasma exosomes may be a potential biomarker for atopic dermatitis in pediatric patients. Exp Ther Med. 2021; 21(5):489. PMC: 8005743. DOI: 10.3892/etm.2021.9920. View

Salomon C, Guanzon D, Scholz-Romero K, Longo S, Correa P, Illanes S . Placental Exosomes as Early Biomarker of Preeclampsia: Potential Role of Exosomal MicroRNAs Across Gestation. J Clin Endocrinol Metab. 2017; 102(9):3182-3194. DOI: 10.1210/jc.2017-00672. View

Lyons S, Fay M, Ivanov P . The role of RNA modifications in the regulation of tRNA cleavage. FEBS Lett. 2018; 592(17):2828-2844. PMC: 6986807. DOI: 10.1002/1873-3468.13205. View

Wei J, Blenkiron C, Tsai P, James J, Chen Q, Stone P . Placental trophoblast debris mediated feto-maternal signalling via small RNA delivery: implications for preeclampsia. Sci Rep. 2017; 7(1):14681. PMC: 5665858. DOI: 10.1038/s41598-017-14180-8. View

Teng F, Fussenegger M . Shedding Light on Extracellular Vesicle Biogenesis and Bioengineering. Adv Sci (Weinh). 2021; 8(1):2003505. PMC: 7788585. DOI: 10.1002/advs.202003505. View

Cindrova-Davies T, Sanders D, Burton G, Charnock-Jones D . Soluble FLT1 sensitizes endothelial cells to inflammatory cytokines by antagonizing VEGF receptor-mediated signalling. Cardiovasc Res. 2010; 89(3):671-9. PMC: 3028975. DOI: 10.1093/cvr/cvq346. View

Chiou N, Kageyama R, Ansel K . Selective Export into Extracellular Vesicles and Function of tRNA Fragments during T Cell Activation. Cell Rep. 2018; 25(12):3356-3370.e4. PMC: 6392044. DOI: 10.1016/j.celrep.2018.11.073. View

Magee L, Nicolaides K, von Dadelszen P . Preeclampsia. N Engl J Med. 2022; 386(19):1817-1832. DOI: 10.1056/NEJMra2109523. View

Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P . The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 2012; 41(Database issue):D590-6. PMC: 3531112. DOI: 10.1093/nar/gks1219. View

10.

Zeisler H, Llurba E, Chantraine F, Vatish M, Staff A, Sennstrom M . Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. N Engl J Med. 2016; 374(1):13-22. DOI: 10.1056/NEJMoa1414838. View

11.

Cerdeira A, Kandzija N, Pargmae P, Cooke W, James T, Redman C . Circulating soluble fms-like tyrosine kinase-1 is placentally derived in normal pregnancy: First in vivo evidence. Pregnancy Hypertens. 2019; 16:145-147. DOI: 10.1016/j.preghy.2019.03.013. View

12.

Redman C, Staff A, Roberts J . Syncytiotrophoblast stress in preeclampsia: the convergence point for multiple pathways. Am J Obstet Gynecol. 2021; 226(2S):S907-S927. DOI: 10.1016/j.ajog.2020.09.047. View

13.

Brown M, Magee L, Kenny L, Karumanchi S, McCarthy F, Saito S . Hypertensive Disorders of Pregnancy: ISSHP Classification, Diagnosis, and Management Recommendations for International Practice. Hypertension. 2018; 72(1):24-43. DOI: 10.1161/HYPERTENSIONAHA.117.10803. View

14.

Motta-Mejia C, Kandzija N, Zhang W, Mhlomi V, Cerdeira A, Burdujan A . Placental Vesicles Carry Active Endothelial Nitric Oxide Synthase and Their Activity is Reduced in Preeclampsia. Hypertension. 2017; 70(2):372-381. PMC: 5507817. DOI: 10.1161/HYPERTENSIONAHA.117.09321. View

15.

Knight M, Redman C, Linton E, Sargent I . Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies. Br J Obstet Gynaecol. 1998; 105(6):632-40. DOI: 10.1111/j.1471-0528.1998.tb10178.x. View

16.

Levine R, Maynard S, Qian C, Lim K, England L, Yu K . Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004; 350(7):672-83. DOI: 10.1056/NEJMoa031884. View

17.

Dragovic R, Collett G, Hole P, Ferguson D, Redman C, Sargent I . Isolation of syncytiotrophoblast microvesicles and exosomes and their characterisation by multicolour flow cytometry and fluorescence Nanoparticle Tracking Analysis. Methods. 2015; 87:64-74. PMC: 4641874. DOI: 10.1016/j.ymeth.2015.03.028. View

18.

Rasmussen M, Reddy M, Nolan R, Camunas-Soler J, Khodursky A, Scheller N . RNA profiles reveal signatures of future health and disease in pregnancy. Nature. 2022; 601(7893):422-427. PMC: 8770117. DOI: 10.1038/s41586-021-04249-w. View

19.

Li G, Manning A, Bagi A, Yang X, Gokulnath P, Spanos M . Distinct Stress-Dependent Signatures of Cellular and Extracellular tRNA-Derived Small RNAs. Adv Sci (Weinh). 2022; 9(17):e2200829. PMC: 9189662. DOI: 10.1002/advs.202200829. View

20.

Liu X, Fei H, Yang C, Wang J, Zhu X, Yang A . Trophoblast-Derived Extracellular Vesicles Promote Preeclampsia by Regulating Macrophage Polarization. Hypertension. 2022; 79(10):2274-2287. DOI: 10.1161/HYPERTENSIONAHA.122.19244. View