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Hum. Reprod. Advance Access originally published online on April 23, 2008
Human Reproduction 2008 23(6):1447-1456; doi:10.1093/humrep/den110
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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A distinct cohort of the TGFβ superfamily members expressed in human endometrium regulate decidualization

Chelsea J. Stoikos1,2,3, Craig A. Harrison1, Lois A. Salamonsen1 and Evdokia Dimitriadis1

1 Prince Henry's Institute of Medical Research, PO Box 5152, Clayton, Victoria 3168, Australia 2 Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria 3168, Australia

3 Correspondence address. Tel: +61-3-9594-3249; Fax: +61-3-9594-6152; E-mail: chelsea.stoikos{at}princehenrys.org

BACKGROUND: Successful blastocyst implantation requires the differentiation of human endometrial stromal cells (HESC), a process known as decidualization. Activin A, a transforming growth factor β (TGFβ) superfamily member, enhances HESC decidualization and localizes to decidual cells in human endometrium. Other TGFβ superfamily members, including BMP2, BMP4, BMP7, GDF5, GDF8, GDF11, TGFβs and Nodal, may also play a role during decidualization. This study aimed to identify these TGFβ family members in human endometrium, and to determine whether they are involved in human decidualization.

METHODS: Protein localization of TGFβ family members was examined in secretory phase human endometrium and first trimester decidua by immunohistochemistry. mRNA expression was examined in HESC. Activin inhibitors (Activin-M108A/SB431542) with differing specificities for the other TGFβ members under consideration were applied during HESC decidualization in vitro. The secretion levels of potential TGFβ superfamily members were measured during decidualization, and recombinant proteins added to examine their effect.

RESULTS: This study has identified BMP2, BMP4, BMP7, GDF5, GDF8 and GDF11 but not Nodal in secretory phase human endometrium, but only BMP2, GDF5 and TGFβ1 protein were detected in decidual cells. All ligands except Nodal were expressed by cultured HESC. Both inhibitors significantly reduced decidualization validating the role of activin, but potentially also other TGFβ members, during decidualization. BMP2 and TGFβ1 secretion increased during HESC decidualisation and exogenous administration of these proteins significantly enhanced decidualization in vitro.

CONCLUSIONS: Like activin, BMP2 and TGFβ1 are likely to be involved in HESC decidualization. This is the first study to identify and localize BMP4, BMP7, GDF5, GDF8 and GDF11 in secretory phase human endometrium. Understanding the factors critical for the implantation process is needed for improving fertility and pregnancy outcomes.

Key words: human endometrium/growth factors (activins, BMP, TGFβ)/implantation/decidualization

Submitted on October 28, 2007; resubmitted on February 28, 2008; accepted on March 12, 2008.


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