title: Maternal peripheral blood natural killer cells incorporate placenta-associated microRNAs during pregnancy.
abstract: Although recent studies have demonstrated that microRNAs (miRNAs or miRs) regulate fundamental natural killer (NK) cellular processes, including cytotoxicity and cytokine production, little is known about the miRNA-gene regulatory relationships in maternal peripheral blood NK (pNK) cells during pregnancy. In the present study, to determine the roles of miRNAs within gene regulatory networks of maternal pNK cells, we performed comprehensive miRNA and gene expression profiling of maternal pNK cells using a combination of reverse transcription quantitative PCR (RT-qPCR)-based miRNA array and DNA microarray analyses and analyzed the differential expression levels between first- and third-trimester pNK cells. Furthermore, we constructed regulatory networks for miRNA-mediated gene expression in pNK cells during pregnancy by Ingenuity Pathway Analysis (IPA). PCR-based array analysis revealed that the placenta-derived miRNAs [chromosome 19 miRNA cluster (C19MC) miRNAs] were detected in pNK cells during pregnancy. Twenty-five miRNAs, including six C19MC miRNAs, were significantly upregulated in the third- compared to first-trimester pNK cells. The rapid clearance of C19MC miRNAs also occurred in the pNK cells following delivery. Nine miRNAs, including eight C19MC miRNAs, were significantly downregulated in the post-delivery pNK cells compared to those of the third-trimester. DNA microarray analysis identified 69 NK cell function-related genes that were differentially expressed between the first- and third-trimester pNK cells. On pathway and network analysis, the observed gene expression changes of pNK cells likely contribute to the increase in the cytotoxicity, as well as the cell cycle progression of third- compared to first-trimester pNK cells. Thirteen of the 69 NK cell function-related genes were significantly downregulated between the first- and third-trimester pNK cells. Nine of the 13 downregulated NK-function-associated genes were in silico target candidates of 12 upregulated miRNAs, including C19MC miRNA miR-512-3p. The results of this study suggest that the transfer of placental C19MC miRNAs into maternal pNK cells occurs during pregnancy. The present study provides new insight into maternal NK cell functions.
authors.affiliation: Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329‑0498, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ishida
authors.affiliation: Department of Molecular Medicine and Anatomy, Graduate School of Medicine, Nippon Medical School, Tokyo 113‑8602, Japan.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329‑0498, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Ohkuchi
authors.affiliation: Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329‑0498, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kuwata
authors.affiliation: Department of Molecular Medicine and Anatomy, Graduate School of Medicine, Nippon Medical School, Tokyo 113‑8602, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshitake
authors.affiliation: Department of Molecular Medicine and Anatomy, Graduate School of Medicine, Nippon Medical School, Tokyo 113‑8602, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yuge
authors.affiliation: Department of Molecular Medicine and Anatomy, Graduate School of Medicine, Nippon Medical School, Tokyo 113‑8602, Japan.
authors.forename: Takami
authors.initials: T
authors.lastname: Takizawa
authors.affiliation: Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329‑0498, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Matsubara
authors.affiliation: Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329‑0498, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toyama, Toyama 930‑0194, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Molecular Medicine and Anatomy, Graduate School of Medicine, Nippon Medical School, Tokyo 113‑8602, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takizawa
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism*; D035683:MicroRNAs / Q000097:blood*; D036801:Parturition / Q000097:blood*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy / Q000097:blood*; D011263:Pregnancy Trimester, Third / Q000097:blood*
chemical_list: D035683:MicroRNAs
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