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http://dx.doi.org/10.14348/molcells.2021.0211

Trophoblast Cell Subtypes and Dysfunction in the Placenta of Individuals with Preeclampsia Revealed by Single-Cell RNA Sequencing  

Zhou, Wenbo (International Genome Center, Jiangsu University)
Wang, Huiyan (Changzhou Maternal and Child Health Care Hospital, Nanjing Medical University)
Yang, Yuqi (Changzhou Maternal and Child Health Care Hospital, Nanjing Medical University)
Guo, Fang (Changzhou Maternal and Child Health Care Hospital, Nanjing Medical University)
Yu, Bin (Changzhou Maternal and Child Health Care Hospital, Nanjing Medical University)
Su, Zhaoliang (International Genome Center, Jiangsu University)
Publication Information
Molecules and Cells / v.45, no.5, 2022 , pp. 317-328 More about this Journal
Abstract
Trophoblasts, important functional cells in the placenta, play a critical role in maintaining placental function. The heterogeneity of trophoblasts has been reported, but little is known about the trophoblast subtypes and distinctive functions during preeclampsia (PE). In this study, we aimed to gain insight into the cell type-specific transcriptomic changes by performing unbiased single-cell RNA sequencing (scRNA-seq) of placental tissue samples, including those of patients diagnosed with PE and matched healthy controls. A total of 29,006 cells were identified in 11 cell types, including trophoblasts and immune cells, and the functions of the trophoblast subtypes in the PE group and the control group were also analyzed. As an important trophoblast subtype, extravillous trophoblasts (EVTs) were further divided into 4 subgroups, and their functions were preliminarily analyzed. We found that some biological processes related to pregnancy, hormone secretion and immunity changed in the PE group. We also identified and analyzed the regulatory network of transcription factors (TFs) identified in the EVTs, among which 3 modules were decreased in the PE group. Then, through in vitro cell experiments, we found that in one of the modules, CEBPB and GTF2B may be involved in EVT dysfunction in PE. In conclusion, our study showed the different transcriptional profiles and regulatory modules in trophoblasts between placentas in the control and PE groups at the single-cell level; these changes may be involved in the pathological process of PE, providing a new molecular theoretical basis for preeclamptic trophoblast dysfunction.
Keywords
placenta; preeclampsia; RNA sequencing; single-cell; transcriptomes;
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1 Huang, Y., Lin, L., Shen, Z., Li, Y., Cao, H., Peng, L., Qiu, Y., Cheng, X., Meng, M., Lu, D., et al. (2020). CEBPG promotes esophageal squamous cell carcinoma progression by enhancing PI3K-AKT signaling. Am. J. Cancer Res. 10, 3328-3344.
2 Ji, L., Brkic, J., Liu, M., Fu, G., Peng, C., and Wang, Y.L. (2013). Placental trophoblast cell differentiation: physiological regulation and pathological relevance to preeclampsia. Mol. Aspects Med. 34, 981-1023.   DOI
3 Pavlicev, M., Wagner, G.P., Chavan, A.R., Owens, K., Maziarz, J., Dunn-Fletcher, C., Kallapur, S.G., Muglia, L., and Jones, H. (2017). Single-cell transcriptomics of the human placenta: inferring the cell communication network of the maternal-fetal interface. Genome Res. 27, 349-361.   DOI
4 Knofler, M., Haider, S., Saleh, L., Pollheimer, J., Gamage, T., and James, J. (2019). Human placenta and trophoblast development: key molecular mechanisms and model systems. Cell. Mol. Life Sci. 76, 3479-3496.   DOI
5 Kruger, I., Vollmer, M., Simmons, D.G., Elsasser, H.P., Philipsen, S., and Suske, G. (2007). Sp1/Sp3 compound heterozygous mice are not viable: impaired erythropoiesis and severe placental defects. Dev. Dyn. 236, 2235-2244.   DOI
6 Lee, T. and Lee, H. (2021). Shared blood transcriptomic signatures between Alzheimer's disease and diabetes mellitus. Biomedicines 9, 34.   DOI
7 Nakashima, A., Shima, T., Tsuda, S., Aoki, A., Kawaguchi, M., Furuta, A., Yasuda, I., Yoneda, S., Yamaki-Ushijima, A., Cheng, S.B., et al. (2021). Aggrephagy deficiency in the placenta: a new pathogenesis of preeclampsia. Int. J. Mol. Sci. 22, 2432.   DOI
8 Liu, Y., Fan, X., Wang, R., Lu, X., Dang, Y.L., Wang, H., Lin, H.Y., Zhu, C., Ge, H., Cross, J.C., et al. (2018). Single-cell RNA-seq reveals the diversity of trophoblast subtypes and patterns of differentiation in the human placenta. Cell Res. 28, 819-832.   DOI
9 Middleton, P., Shepherd, E., and Gomersall, J.C. (2021). Venous thromboembolism prophylaxis for women at risk during pregnancy and the early postnatal period. Cochrane Database Syst. Rev. 3, CD001689.
10 Moslehi, R., Ambroggio, X., Nagarajan, V., Kumar, A., and Dzutsev, A. (2014). Nucleotide excision repair/transcription gene defects in the fetus and impaired TFIIH-mediated function in transcription in placenta leading to preeclampsia. BMC Genomics 15, 373.   DOI
11 Nirupama, R., Divyashree, S., Janhavi, P., Muthukumar, S.P., and Ravindra, P.V. (2021). Preeclampsia: pathophysiology and management. J. Gynecol. Obstet. Hum. Reprod. 50, 101975.   DOI
12 Peng, Y., Jin, Z., Liu, H., and Xu, C. (2021). Impaired decidualization of human endometrial stromal cells from women with adenomyosis. Biol. Reprod. 104, 1034-1044.   DOI
13 Piccinni, M.P., Raghupathy, R., Saito, S., and Szekeres-Bartho, J. (2021). Cytokines, hormones and cellular regulatory mechanisms favoring successful reproduction. Front. Immunol. 12, 717808.   DOI
14 Redhead, M.L., Portilho, N.A., Felker, A.M., Mohammad, S., Mara, D.L., and Croy, B.A. (2016). The transcription factor NFIL3 is essential for normal placental and embryonic development but not for uterine natural killer (UNK) cell differentiation in mice. Biol. Reprod. 94, 101.
15 Than, N.G., Romero, R., Tarca, A.L., Kekesi, K.A., Xu, Y., Xu, Z., Juhasz, K., Bhatti, G., Leavitt, R.J., Gelencser, Z., et al. (2018). Integrated systems biology approach identifies novel maternal and placental pathways of preeclampsia. Front. Immunol. 9, 1661.   DOI
16 Suo, S., Zhu, Q., Saadatpour, A., Fei, L., Guo, G., and Yuan, G.C. (2018). Revealing the critical regulators of cell identity in the mouse cell atlas. Cell Rep. 25, 1436-1445.e3.   DOI
17 Tekola-Ayele, F., Zeng, X., Ouidir, M., Workalemahu, T., Zhang, C., Delahaye, F., and Wapner, R. (2020). DNA methylation loci in placenta associated with birthweight and expression of genes relevant for early development and adult diseases. Clin. Epigenetics 12, 78.   DOI
18 Li, H., Huang, Q., Liu, Y., and Garmire, L.X. (2020). Single cell transcriptome research in human placenta. Reproduction 160, R155-R167.   DOI
19 Kaitu'u-Lino, T.J., Brownfoot, F.C., Hastie, R., Chand, A., Cannon, P., Deo, M., Tuohey, L., Whitehead, C., Hannan, N.J., and Tong, S. (2017). Activating transcription factor 3 is reduced in preeclamptic placentas and negatively regulates sFlt-1 (soluble fms-like tyrosine kinase 1), soluble endoglin, and proinflammatory cytokines in placenta. Hypertension 70, 1014-1024.   DOI
20 Li, X., Wu, C., Shen, Y., Wang, K., Tang, L., Zhou, M., Yang, M., Pan, T., Liu, X., and Xu, W. (2018). Ten-eleven translocation 2 demethylates the MMP9 promoter, and its down-regulation in preeclampsia impairs trophoblast migration and invasion. J. Biol. Chem. 293, 10059-10070.   DOI
21 Tsang, J.C.H., Vong, J.S.L., Ji, L., Poon, L.C.Y., Jiang, P., Lui, K.O., Ni, Y.B., To, K.F., Cheng, Y.K.Y., Chiu, R.W.K., et al. (2017). Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics. Proc. Natl. Acad. Sci. U. S. A. 114, E7786-E7795.
22 Vento-Tormo, R., Efremova, M., Botting, R.A., Turco, M.Y., Vento-Tormo, M., Meyer, K.B., Park, J.E., Stephenson, E., Polanski, K., Goncalves, A., et al. (2018). Single-cell reconstruction of the early maternal-fetal interface in humans. Nature 563, 347-353.   DOI
23 Xueya, Z., Yamei, L., Sha, C., Dan, C., Hong, S., Xingyu, Y., and Weiwei, C. (2020). Exosomal encapsulation of miR-125a-5p inhibited trophoblast cell migration and proliferation by regulating the expression of VEGFA in preeclampsia. Biochem. Biophys. Res. Commun. 525, 646-653.   DOI
24 Kohan-Ghadr, H.R., Kilburn, B.A., Kadam, L., Johnson, E., Kolb, B.L., Rodriguez-Kovacs, J., Hertz, M., Armant, D.R., and Drewlo, S. (2019). Rosiglitazone augments antioxidant response in the human trophoblast and prevents apoptosis†. Biol. Reprod. 100, 479-494.   DOI
25 Bai, K., Li, X., Zhong, J., Ng, E.H.Y., Yeung, W.S.B., Lee, C.L., and Chiu, P.C.N. (2021). Placenta-derived exosomes as a modulator in maternal immune tolerance during pregnancy. Front. Immunol. 12, 671093.   DOI
26 Chang, C.W., Wakeland, A.K., and Parast, M.M. (2018). Trophoblast lineage specification, differentiation and their regulation by oxygen tension. J. Endocrinol. 236, R43-R56.   DOI
27 Jiang, F., Yang, Y., Li, J., Li, W., Luo, Y., Li, Y., Zhao, H., Wang, X., Yin, G., and Wu, G. (2015). Partial least squares-based gene expression analysis in preeclampsia. Genet. Mol. Res. 14, 6598-6604.   DOI
28 Marsh, B. and Blelloch, R. (2020). Single nuclei RNA-seq of mouse placental labyrinth development. Elife 9, e60266.   DOI
29 Yang, Y., Guo, F., Peng, Y., Chen, R., Zhou, W., Wang, H., OuYang, J., Yu, B., and Xu, Z. (2021). Transcriptomic profiling of human placenta in gestational diabetes mellitus at the single-cell level. Front. Endocrinol. (Lausanne) 12, 679582.   DOI
30 Munro, S.K., Balakrishnan, B., Lissaman, A.C., Gujral, P., and Ponnampalam, A.P. (2021). Cytokines and pregnancy: potential regulation by histone deacetylases. Mol. Reprod. Dev. 88, 321-337.   DOI
31 Abbas, Y., Turco, M.Y., Burton, G.J., and Moffett, A. (2020). Investigation of human trophoblast invasion in vitro. Hum. Reprod. Update 26, 501-513.   DOI
32 Selvaraju, S., Ramya, L., Parthipan, S., Swathi, D., Binsila, B.K., and Kolte, A.P. (2021). Deciphering the complexity of sperm transcriptome reveals genes governing functional membrane and acrosome integrities potentially influence fertility. Cell Tissue Res. 385, 207-222.   DOI
33 Aibar, S., Gonzalez-Blas, C.B., Moerman, T., Huynh-Thu, V.A., Imrichova, H., Hulselmans, G., Rambow, F., Marine, J.C., Geurts, P., Aerts, J., et al. (2017). SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083-1086.   DOI
34 Pique-Regi, R., Romero, R., Tarca, A.L., Sendler, E.D., Xu, Y., Garcia-Flores, V., Leng, Y., Luca, F., Hassan, S.S., and Gomez-Lopez, N. (2019). Single cell transcriptional signatures of the human placenta in term and preterm parturition. Elife 8, e52004.   DOI
35 Ridder, A., Giorgione, V., Khalil, A., and Thilaganathan, B. (2019). Preeclampsia: the relationship between uterine artery blood flow and trophoblast function. Int. J. Mol. Sci. 20, 3263.   DOI
36 Aran, D., Looney, A.P., Liu, L., Wu, E., Fong, V., Hsu, A., Chak, S., Naikawadi, R.P., Wolters, P.J., Abate, A.R., et al. (2019). Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat. Immunol. 20, 163-172.   DOI
37 Brenner, E., Tiwari, G.R., Kapoor, M., Liu, Y., Brock, A., and Mayfield, R.D. (2020). Single cell transcriptome profiling of the human alcohol-dependent brain. Hum. Mol. Genet. 29, 1144-1153.   DOI
38 Butler, A., Hoffman, P., Smibert, P., Papalexi, E., and Satija, R. (2018). Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411-420.   DOI