Role of the cell cycle in regression of the corpus luteum

Abstract

The corpus luteum contains differentiated steroidogenic cells that have exited the cell cycle of proliferation. In some tissues, deletion of quiescent, differentiated cells by apoptosis in response to injury or pathology is preceded by reentry into the cell cycle. We tested whether luteal cells reenter the cell cycle during the physiological process of luteolysis. Ovaries were obtained after injection of cows with a luteolytic dose of prostaglandin F 2a (PGF). In luteal sections, cells co-staining for markers of cell proliferation (MKI67) and apoptosis (cPARP1) increased 24 h after PGF, indicating that cells that reenter the cell cycle undergo apoptosis. The percent of steroidogenic cells (CYP11A1-positive) co-staining for MKI67 increased after PGF, while co-staining of non-steroidogenic cells did not change. Dispersed luteal cells were stained with Nile Red to distinguish lipid-rich steroidogenic cells from nonsteroidogenic cells and co-stained for DNA. Flow cytometry showed that the percent of steroidogenic cells progressing through the cell cycle and undergoing apoptosis increased after PGF. Culturing luteal cells induced reentry of steroidogenic cells into the cell cycle, providing a model to test the influence of the cell cycle on susceptibility to apoptosis. Blocking cells early in the cell cycle using inhibitors reduced cell death in response to treatment with the apoptosis-inducing protein, Fas ligand (FASL). Progesterone treatment reduced progression through the cell cycle and decreased FASL-induced apoptosis. In summary, steroidogenic cells reenter the cell cycle upon induction of luteal regression. While quiescent cells are resistant to apoptosis, entry into the cell cycle promotes susceptibility to apoptosis.

Effects of IL8 and immune cells on the regulation of luteal progesterone secretion

“…These observations support our earlier findings (Liptak et al 2005) that activated immune cells may contribute a factor (or factors) that impair steroidogenesis in response to LH. It is known that activated monocytes produce inflammatory cytokines, nitric oxide, and reactive oxygen species (Murray & Wynn 2011, Zhou et al 2014) all of which may contribute individually or in combination to the inhibition of progesterone synthesis (Al-Gubory et al 2012, Quirk et al 2013, Skarzynski et al 2013). In the in vivo setting, activated monocytes may also secrete matrix metalloproteinases that contribute to the degradation of the extracellular matrix (Murray & Wynn 2011), which could facilitate the recruitment of additional inflammatory cells to the regressing corpus luteum.…”

“…PGF has been shown to act indirectly at the vascular level to cause disruption of luteal capillaries (Maroni & Davis 2011) and apoptosis of capillary endothelial cells (Henkes et al 2008). PGF has also been implicated in the initiation of luteal cell apoptosis in vivo (Davis & Rueda 2002, Quirk et al 2013); however, PGF alone cannot directly reduce the viability of luteal cells in vitro (Davis & Rueda 2002, Kawaguchi et al 2013). Thus, other mechanisms must be activated for luteolysis to proceed through both the functional (loss of progesterone secretion) and structural (apoptosis and tissue remodeling) stages of regression.…”

The effects of dexamethasone administered during pregnancy on the postpartum spiny mouse ovary

“…It is interesting to note that differentiated, nonproliferating luteal cells show the presence of PCNA. Several previous studies also reported expression of cell proliferation markers PCNA or Ki67 during rat [ 38 ], mare [ 39 ] and cow [ 40 ] luteal regression. It is suggested that the decline in progesterone synthesis during natural CL luteolysis may promote re-entry of luteal cells into the cell cycle and susceptibility to apoptosis [ 40 ].…”

Inflammation and angiogenesis in the corpus luteum

“…6 In addition to steroidogenic cells, the CL contains endothelial cells (EC), pericytes, fibroblasts and immune cells. [7][8][9] During the estrous cycle, the CL is developed from the ovulatory follicle and undergoes remarkable growth, differentiation and remodeling. 10 If an oocyte is not fertilized, the CL will regress, with apoptosis of luteal cells and a decline in P4 synthesis.…”