title: Estrogen-inducible sFRP5 inhibits early B-lymphopoiesis in vivo, but not during pregnancy.
abstract: Mammals have evolved to protect their offspring during early fetal development. Elaborated mechanisms induce tolerance in the maternal immune system for the fetus. Female hormones, mainly estrogen, play a role in suppressing maternal lymphopoiesis. However, the molecular mechanisms involved in the maternal immune tolerance are largely unknown. Here, we show that estrogen-induced soluble Frizzled-related proteins (sFRPs), and particularly sFRP5, suppress B-lymphopoiesis in vivo in transgenic mice. Mice overexpressing sFRP5 had fewer B-lymphocytes in the peripheral blood and spleen. High levels of sFRP5 inhibited early B-cell differentiation in the bone marrow (BM), resulting in the accumulation of cells with a common lymphoid progenitor (CLP) phenotype. Conversely, sFRP5 deficiency reduced the number of hematopoietic stem cells (HSCs) and primitive lymphoid progenitors in the BM, particularly when estrogen was administered. Furthermore, a significant reduction in CLPs and B-lineage-committed progenitors was observed in the BM of sfrp5-null pregnant females. We concluded that, although high sFRP5 expression inhibits B-lymphopoiesis in vivo, physiologically, it contributes to the preservation of very primitive lymphopoietic progenitors, including HSCs, under high estrogen levels. Thus, sFRP5 regulates early lympho-hematopoiesis in the maternal BM, but the maternal-fetal immune tolerance still involves other molecular mechanisms that remain to be uncovered.
authors: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Takafumi
authors: T
authors: Yokota
authors: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Kenji
authors: K
authors: Oritani
authors: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Takao
authors: T
authors: Sudo
authors: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Tomohiko
authors: T
authors: Ishibashi
authors: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Yukiko
authors: Y
authors: Doi
authors: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Yoko
authors: Y
authors: Habuchi
authors: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Michiko
authors: M
authors: Ichii
authors: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Kentaro
authors: K
authors: Fukushima
authors: DNA-chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors: Daisuke
authors: D
authors: Okuzaki
authors: Kyowa Hakko Kirin California, Inc. Research Divisions, CA, USA.
authors: Kazuma
authors: K
authors: Tomizuka
authors: Kyowa Hakko Kirin Co, Ltd. Biologics Research Laboratories, Research Division, Machida, Tokyo, Japan.
authors: Kengo
authors: K
authors: Yamawaki
authors: Kyowa Hakko Kirin Co, Ltd. Bio Process Research and Development Laboratories, Takasaki, Gunma, Japan.
authors: Makoto
authors: M
authors: Kakitani
authors: TransGenic Inc. 7-1-14 Minatojima-minami, Chuo, Kobe, Japan.
authors: Akihiko
authors: A
authors: Shimono
authors: Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Eiichi
authors: E
authors: Morii
authors: Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors: Paul W
authors: PW
authors: Kincade
authors: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Yuzuru
authors: Y
authors: Kanakura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019070:Cell Lineage; D004967:Estrogens / Q000276:immunology*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D054502:Histocompatibility, Maternal-Fetal / Q000276:immunology; D007108:Immune Tolerance; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology*; D008297:Male; D008431:Maternal-Fetal Exchange / Q000276:immunology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011247:Pregnancy; D015854:Up-Regulation; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004967:Estrogens; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C487972:Sfrp5 protein, mouse
keywords: B-lymphopoiesis; Bone marrow; Estrogen; Hematopoietic stem cells; Immune tolerance; Lymphoid progenitors; Pregnancy; Soluble Frizzled-related proteins