A distinct cohort of the TGFbeta 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 beta (TGFbeta) superfamily member, enhances HESC decidualization and localizes to decidual cells in human endometrium. Other TGFbeta superfamily members, including BMP2, BMP4, BMP7, GDF5, GDF8, GDF11, TGFbetas and Nodal, may also play a role during decidualization. This study aimed to identify these TGFbeta family members in human endometrium, and to determine whether they are involved in human decidualization.


METHODS
Protein localization of TGFbeta 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 TGFbeta members under consideration were applied during HESC decidualization in vitro. The secretion levels of potential TGFbeta 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 TGFbeta1 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 TGFbeta members, during decidualization. BMP2 and TGFbeta1 secretion increased during HESC decidualisation and exogenous administration of these proteins significantly enhanced decidualization in vitro.


CONCLUSIONS
Like activin, BMP2 and TGFbeta1 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.
Stoikos
Chelsea J
CJ
Prince Henry's Institute of Medical Research, PO Box 5152, Clayton, Victoria 3168, Australia. chelsea.stoikos@princehenrys.org
Harrison
Craig A
CA
Salamonsen
Lois A
LA
Dimitriadis
Evdokia
E
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis; D003656:Decidua / Q000166:cytology / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D055428:Growth Differentiation Factor 5; D055412:Growth Differentiation Factors; D006801:Humans; D007150:Immunohistochemistry; D008183:Luteal Phase; D055435:Myostatin; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
C525718:BMP2 protein, human; C525809:BMP4 protein, human; C525819:BMP7 protein, human; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; C492266:GDF11 protein, human; C525893:GDF5 protein, human; D055428:Growth Differentiation Factor 5; D055412:Growth Differentiation Factors; C525911:MSTN protein, human; D055435:Myostatin; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1