Epithelial cell protein milk fat globule-epidermal growth factor 8 and human chorionic gonadotropin regulate stromal cell apoptosis in the human endometrium

Fertil Steril. 2012 Dec;98(6):1549-56.e3. doi: 10.1016/j.fertnstert.2012.07.1127. Epub 2012 Aug 24.


Objective: To study the regulation of apoptosis in human endometrial cells. The specific aims were to determine whether milk fat globule-epidermal growth factor 8 (MFG-E8), a novel endometrial epithelial protein, modulates caspase activation and DNA fragmentation; and to examine whether hCG, an early embryonic product, regulates Bax and Bcl-2 equilibrium, as well as MFG-E8 expression.

Design: Primary cultures of human endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs).

Setting: Academic center.

Patient(s): Ovulatory women aged 21-30 years.

Intervention(s): Treatment with MFG-E8 and hCG.

Main outcome measure(s): Apoptotic activity was quantified using a luciferase assay. Deoxyribonucleic acid fragmentation was detected by TUNEL assay. Bax, Bcl-2, and MFG-E8 messenger RNA expression levels were determined by quantitative reverse transcription-polymerase chain reaction. Immunocytochemistry was used to establish cell purity and presence of MFG-E8 and hCG-R (receptor) proteins.

Result(s): Endometrial epithelial cells were cytokeratin(+), vimentin(-), MFG-E8(+), and hCG-R(+), whereas ESC were vimentin(+), cytokeratin(-), MFG-E8(-), and hCG-R(+). Treatment of ESC with MFG-E8 resulted in a 13-fold increase in caspase activity and a 30-fold increase in TUNEL. On the other hand, hCG decreased messenger RNA expression of Bax in ESC.

Conclusion(s): Milk fat globule-epidermal growth factor 8 has proapoptotic activity, suggesting participation in endometrial remodeling via an epithelial-stromal cell paracrine effect. Conversely, pregnancy levels of hCG has opposite effects on stromal cells.

MeSH terms

  • Adult
  • Antigens, Surface / metabolism*
  • Apoptosis / physiology
  • Caspases / metabolism
  • Cells, Cultured
  • Chorionic Gonadotropin / metabolism*
  • Endometrium / cytology*
  • Endometrium / metabolism*
  • Enzyme Activation
  • Epithelial Cells / metabolism*
  • Female
  • Humans
  • Milk Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Stromal Cells / cytology
  • Young Adult
  • bcl-2-Associated X Protein


  • Antigens, Surface
  • BAX protein, human
  • Chorionic Gonadotropin
  • MFGE8 protein, human
  • Milk Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • Caspases