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Brain-Derived Neurotrophic Factor/Tyrosine Kinase B Signaling Regulates Human Trophoblast Growth in an in Vivo Animal Model of Ectopic Pregnancy.
MedLine Citation:
PMID:  21239439     Owner:  NLM     Status:  Publisher    
Although medical treatment of unruptured ectopic pregnancy using methotrexate has been established, development of more potent and safer medical treatment is needed due to limited indications and side effects of methotrexate. Brain-derived neurotrophic factor (BDNF) signals through its receptor tyrosine kinase B (TrkB) to regulate the growth of malignant trophoblastic, choriocarcinoma cell. We investigated possible involvement of this signaling system in nonmalignant human trophoblast growth in both ectopic and intrauterine pregnancy. Here, we demonstrated the expression of BDNF in syncytiotrophoblasts and extravillous trophoblasts (EVTs) together with TrkB in cytotrophoblasts and EVTs in human placental villi during both normal and ectopic pregnancies. Treatment of cultured villous explants with soluble TrkB ectodomain or a Trk receptor inhibitor K252a suppressed cytotrophoblast differentiation by inhibiting EVT outgrowth reflected by decreased levels of an EVT marker, human leukocyte antigen-G. These inhibitors also decreased cytotrophoblast proliferation and cellular viability based on histopathological analyses and monitoring glucose metabolism, together with increased apoptosis in cytotrophoblasts based on in situ terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end-labeling and caspase-3/7 assays. After xenotransplantation of human placental villi into SCID mice as an in vivo model of ectopic pregnancy, treatment with K252a suppressed transplanted villi growth as reflected by decreased cytotrophoblast differentiation and proliferation, reduced tissue levels of chorionic gonadotropin-β, and increased apoptosis and caspase-3/7 activities. Thus, paracrine signaling by the BDNF/TrkB system is important for human cytotrophoblast differentiation, proliferation, and survival, and inhibition of BDNF/TrkB signaling in cytotrophoblasts could provide a novel medical treatment for ectopic pregnancy.
Kazuhiro Kawamura; Nanami Kawamura; Yukiyo Kumazawa; Jin Kumagai; Toshio Fujimoto; Toshinobu Tanaka
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-1-14
Journal Detail:
Title:  Endocrinology     Volume:  -     ISSN:  1945-7170     ISO Abbreviation:  -     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-1-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0375040     Medline TA:  Endocrinology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Departments of Obstetrics and Gynecology (K.K., N.K., Y.K., J.K., T.F., T.T.) and Dermatology and Plastic Surgery (N.K.), Akita University School of Medicine, Akita 010-8543, Japan.
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