Epidermal Growth Factor and Transforming Growth Factor-α Stimulate the Proliferation of Mouse Uterine Stromal Cells

Abstract

-Growth factors produced in the uterine endometrium are considered to be involved in the proliferation of the mouse uterine stromal cells induced by estradiol-17 β (E 2 ) and progesterone (P). The effect of epidermal growth factor (EGF) and transforming growth factor-α (TGF-α ), one of EGF-related growth factors, on the proliferation of mouse uterine stromal cells was studied in a serum-free culture. The growth of the uterine stromal cells was measured by MTT assay. EGF was found to increase the number of uterine stromal cells in a dose-dependent manner. The DNA-replicating cells were investigated using the immunocytochemical detection of bromodeoxyuridine (BrdU)-labeled cells. EGF and TGF-α increased the percentage of BrdU-labeled cells in a dose-dependent manner. Administration of the combination of E 2 (10 -9 M) and P (10 -7 M) for 2 days increased the percentage of BrdU-labeled cells 2.3-fold. The stimulatory effect of EGF, TGF-α and the combination of E 2 and P on DNA replication in the uterine stromal cells was repressed by RG-13022 (10 -5 M, the inhibitor of the EGF receptor tyrosine kinase). RT-PCR analysis of EGF-receptor-, TGF-α -, and EGF-mRNA was carried out in the cultured uterine stromal cells, and revealed the expression of those mRNAs. These data supported the hypothesis that uterine endometrial stromal growth induced by sex steroids required the EGF family of ligands such as EGF and TGF-α , both produced in the stromal cells, acting for DNA synthesis through EGF receptors.

Estradiol, Progesterone, and Transforming Growth Factor α Regulate Insulin-Like Growth Factor Binding Protein-3 (IGFBP3) Expression in Mouse Endometrial Cells

“…We previously showed that TGFα acts as a mitogenic factor in endometrial stromal cells (Komatsu et al, 2003). In the present study, we demonstrated for the first time that TGFα decreases IGFBP3 expression in mouse endometrial stromal cells.…”

“…P4 stimulates the proliferation of endometrial stromal cells in the presence of estrogen (Komatsu et al, 2003), although estrogen alone does not stimulate proliferation (Quarmby and Korach, 1984). P4 alone increased Igfbp3 mRNA expression in endometrial stromal cells, while P4 had no effect on Igfbp3 mRNA expression in endometrial epithelial cells.…”

“…Uterine epithelial and stromal cells were isolated according to methods used in previous studies (Ross et al, 1993;Shiraga et al, 1997;Komatsu et al, 2003). Isolated uterine epithelial cells were seeded on collagen-coated culture wells at a density of about 5×10 4 cells/cm 2 .…”

Relevant aspects of the influence of chosen growth factors on the activity of the female reproductive system

“…Wykazano istotne różnice w profilu ich ekspresji determinowane zmianami stężenia progesteronu i estrogenu (23,32,35). Białka należące do rodziny EGF zaangażowane są w procesy indukcji hormonalnej, działając stymulująco na wzrost komórek macicy (32,35,62). Komatsu i wsp.…”

“…Komatsu i wsp. (35) wykazali ich istotny wpływ na proliferację komórek błony ślu-zowej macicy u myszy. W endometrium suk poziom transkrypcji oraz lokalizacja białek TGF-α, jak i EGFR różni się w zależności od fazy cyklu płciowego (32,62).…”