Regulation of Ovarian Cell Growth through the Local Production of Transforming Growth Factor-α by Theca Cells*

Abstract

The rapid proliferation of a tissue often requires the local production of a specific growth factor. The ovarian follicle is a rapidly growing tissue which contains two primary somatic cell types, granulosa cells and theca cells. Theca cells and granulosa cells were isolated from bovine ovaries and cultured to assess the possible local production of a growth factor within the ovarian follicle. Serum-free conditioned medium from theca cells, but not from granulosa cells, was found to contain a component that specifically bound to the epidermal growth factor (EGF) receptor. Therefore, theca cells appear to produce an EGF-like substance as a potential regulator of follicle cell growth. This result provides physiological significance to the previous observation that granulosa cells contain EGF receptors and respond to EGF to increase cell proliferation. Transforming growth factor-alpha (TGF alpha) is a protein that is structurally and functionally related to EGF and binds to the EGF receptor. Using a molecular probe to TGF alpha, theca cells were found to express the TGF alpha gene, which is consistent with the presence of an EGF-like substance in conditioned medium, but granulosa cells had no detectable TGF alpha gene expression. Similar analysis with a molecular probe to EGF demonstrated the apparent lack of EGF gene expression in theca cells or granulosa cells. As previously demonstrated with granulosa cells, the data presented indicate that theca cells also contain high affinity EGF receptors. TGF alpha was found to stimulate the growth of both granulosa and theca cells. These observations imply that within the ovarian follicle TGF alpha is produced by theca cells, which can subsequently have both a paracrine and an autocrine role in regulating follicle cell proliferation. Results presented demonstrate production of TGF alpha by a normal adult mesenchymal tissue and provide an example of a growth factor-mediated mesenchymal-epithelial cell interaction between theca cells and granulosa cells.

Effects of transforming growth factors-alpha and -beta on proliferation and apoptosis of rat theca-interstitial cells

“…Most reports focused on granulosa cells, in which effects of TGFs on proliferation seemed to be species-dependent. TGF-(and/or EGF) stimulated proliferation in the majority of studied species including bovine, porcine, and human granulosa cells (Gospodarowicz & Bialecki 1979, May et al 1988, Skinner & Coffey 1988, but had no effect on rat cells (Bendell & Dorrington 1990). In contrast, TGFstimulated proliferation of rat granulosa cells (Dorrington et al 1988), but had no mitogenic activity of cells from cow or pig (May et al 1988, Skinner et al 1987.…”

“…Their receptors have been detected in ovarian cells of many species, including chicken, rat and human (Onagbesan et al 1994a, Scurry et al 1994, McWilliam et al 1995, Tekpetey et al 1995, Onagbesan & Peddie 1998. Expression of TGF-gene and production of TGF-has been demonstrated in granulosa and theca cells from various species (Kudlow et al 1987, Skinner & Coffey 1988, Onagbesan et al 1994a). …”

“…At present, the role of TGF-and TGF-in the regulation of thecal growth is uncertain and the results of in vitro and in vivo studies are contradictory. Under various experimental conditions, TGF-either stimulated thecal proliferation or had no effect on this process (Foghi et al 1997, Skinner & Coffey 1988, Campbell 1999. TGF-, on the other hand, suppressed thymidine incorporation, but had no effect on the cell number (Roberts & Skinner 1991).…”

Localization of transforming growth factor alpha and its receptor in gastric mucosal cells. Implications for a regulatory role in acid secretion and mucosal renewal.

“…TGFa is no longer regarded simply as an embryonic growth factor that is inappropriately expressed in neoplasia, but also as an integral physiological regulator of growth in normal tissues ( 12,32,33). In screening gastrointestinal tissues for TGFa expression, we found relatively abundant levels in the gastric mucosa.…”

Expression of Nerve Growth Factor (NGF) and Its Receptors TrkA and p75 in the Reproductive Organs of Laying Hens

“…Estrogen may induce granulosa cells to produce more FSHR and cooperate with FSH to enhance the expression of luteinizing hormone (LH). LH, in turn, enhances the activity of aromatase, and promotes further synthesis of estrogen (Parrott and Skinner, 1998;Skinner and Coffey, 1988). The activity of aromatase in granulosa cells increases as follicles develop.…”