クマキリ　ジユン   Kumakiri Jiyun   熊切　順    所属   医学部 医学科（東京女子医科大学病院）    職種   教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Reprogramming of the retinoic acid pathway in decidualizing human endometrial stromal cells.
掲載誌名	正式名：PloS one 略　 称：PLoS One ISSNコード：19326203/19326203
掲載区分	国外
巻・号・頁	12(3),pp.e0173035
著者・共著者	Ozaki Rie, Kuroda Keiji, Ikemoto Yuko, Ochiai Asako, Matsumoto Akemi, Kumakiri Jun, Kitade Mari, Itakura Atsuo, Muter Joanne, Brosens Jan J, Takeda Satoru
発行年月	2017
概要	Upon breaching of the endometrial surface epithelium, the implanting embryo embeds in the decidualizing stroma. Retinoic acid (RA), a metabolite of vitamin A, is an important morphogen during embryonic and fetal development, although the role of the RA pathway in the surrounding decidual cells is not understood. Here we show that decidual transformation of human endometrial stromal cells (HESCs) results in profound reprogramming of the RA signaling and metabolism pathways. Differentiating HESCs downregulate the intracellular carrier proteins CRABP2 and FABP5, responsible for transfer and binding of RA to the nuclear receptors RAR and PPARβ/δ, respectively. Furthermore, the expression of RAR, the receptor that mediates the pro-apoptotic effects of RA, was also inhibited. By contrast, PPARβ/δ, which transduces the differentiation responses of RA, was upregulated. Decidualization was also associated with increased expression of retinol-binding protein 4 (RBP4) and various enzymes involved in the metabolism of RA and its precursor, retinaldehyde (Rald), including CYP26A1, DHRS3, and RDH12. Exposure of differentiating HESCs to RA or Rald reversed the inhibition of the CRABP2-RAR pathway, perturbed the expression of decidual marker genes and triggered cell death. Taken together, the data demonstrate that decidualizing HESCs silence RA signaling by downregulating key cytoplasmic binding proteins and by increasing retinoid metabolism. However, excessive RA exposure is toxic for decidual cells and triggers a response that may lead to pregnancy failure.
DOI	10.1371/journal.pone.0173035
PMID	28253328