A distinct cohort of the TGFb superfamily members expressed in human endometrium regulate decidualization

BACKGROUND: Successful blastocyst implantation requires the differentiation of human endometrial stromal cells (HESC), a process known as decidualization. Activin A, a transforming growth factor b (TGFb) superfamily member, enhances HESC decidualization and localizes to decidual cells in human endometrium. Other TGFb superfamily members, including BMP2, BMP4, BMP7, GDF5, GDF8, GDF11, TGFbs and Nodal, may also play a role during decidualization. This study aimed to identify these TGFb family members in human endometrium, and to determine whether they are involved in human decidualization. METHODS: Protein localization of TGFb 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 TGFb members under consideration were applied during HESC decidualization in vitro. The secretion levels of potential TGFb 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 TGFb1 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 TGFb members, during decidualization. BMP2 and TGFb1 secretion increased during HESC decidualisation and exogenous administration of these proteins significantly enhanced decidualization in vitro. CONCLUSIONS: Like activin, BMP2 and TGFb1 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.