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Review
. 2018 Mar 2:9:61.
doi: 10.3389/fendo.2018.00061. eCollection 2018.

Granulosa Cell Apoptosis in the Ovarian Follicle-A Changing View

Sheena L P Regan  1 , Phil G Knight  2 , John L Yovich  1   3 , Yee Leung  4 , Frank Arfuso  1 , Arun Dharmarajan  1
Affiliations
Review

Granulosa Cell Apoptosis in the Ovarian Follicle-A Changing View

Sheena L P Regan et al. Front Endocrinol (Lausanne). .

Abstract

Recent studies challenge the previous view that apoptosis within the granulosa cells of the maturing ovarian follicle is a reflection of aging and consequently a marker for poor quality of the contained oocyte. On the contrary, apoptosis within the granulosa cells is an integral part of normal development and has limited predictive capability regarding oocyte quality or the ensuing pregnancy rate in in vitro fertilization programs. This review article covers our revised understanding of the process of apoptosis within the ovarian follicle, its three phenotypes, the major signaling pathways underlying apoptosis as well as the associated mitochondrial pathways.

Keywords: aging effects; apoptosis signaling; bone morphogenetic proteins; fertility preservation; mitogenic growth; ovarian reserve; receptor of follicle stimulating hormone.

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Figures

Figure 1
Figure 1
Periluteal granulosa cells and cell morphology. Human granulosa cells were collected from a 15 mm follicle during an in vitro fertilization cycle at the time of oocyte collection. The granulosa cells are peri-luteal cells; however, the cytoplasm is still relatively compact compared to granulosa cells collected from ovulatory follicles (5). The granulosa cells have dense clustering of organelles around the large round nucleus (N). The cytoplasm appears granular during the late stages of follicular phase; large lipid droplets contain hormones. Cytoplasmic extrusions or blebbing, which indicates late apoptosis are shown (*); apoptotic bodies (a); organelles (o) clustered around the nucleus. Healthy granulosa cell (N) without blebbing is engulfing a neighboring apoptotic granulosa cell nucleus (N1) via phagocytosis (10). Bar 5 µm.
Figure 2
Figure 2
Schematic diagram of granulosa cell characterization from follicular to luteal phase. In a stage-dependent progression, the granulosa differentiates from a compact 8–15 µm cell with a large round nucleus and relatively small cytoplasm (12). The cytoplasm contains mitochondria, rough endoplasmic reticulum, Golgi apparatus, lipid droplets, and many other organelles (14). As the granulosa cell matures, the organelles proliferate and the cytoplasm expands to accommodate new steroidogenic capacity. A fully luteinized granulosa cell, 25–30 µm, contains a large volume of mitochondria, steroid filled lipid droplets, and smooth/rough endoplasmic reticulum, and has the capacity to produce progesterone directly (8). At any stage of follicular growth the granulosa cell can undergo apoptosis. Early apoptosis is characterized by collapse of the cell membranes and condensation of the chromatin, which often polarizes in the nucleus with the organelles clustered adjacent (15). Early apoptosis in a granulosa cell with an expanded cytoplasm is similarly changed with a greater volume of organelles clustered around a collapsing nucleus. Late stages of apoptosis end with compartmentalization of organelles into blebs and extrusion of apoptotic bodies that may contain nucleic matter.
Figure 3
Figure 3
Apoptosis signaling pathways. Estrogen is a major driver of follicular growth and its effects results in inhibition of apoptosis. There are three main areas of apoptosis inducement: 1. growth factors, 2. death receptors, and 3. cell damage (20). Before antral cavity formation ovarian follicle androgens increase the receptor of follicle stimulating hormone (FSH) expression and high levels of BMPR1B activity, possibly via BMP6 and 7, suppress LHR expression (21). Antiapoptotic FSH induced cAMP–PKA promote ERK1/2 signaling, which increases Bcl-2 and promotes estrogen production in favor of progesterone synthesis (–24). The bone morphogenetic proteins (BMPs) 2, 4, 6, and 7 inhibit progesterone synthesis, which reduces caspase 3, 6, and 7 production during the follicular phase (25). Dysregulation of the BMPs induces granzyme B synthesis leading to increased DNA fragmentation (16). Fas ligand (FasL) and TNFR activity induces caspase 8 induced DNA fragmentation (26). BMP 7 inhibits caspase 3 activity. Estrogen via the estrogen receptor has also been shown to reduce FasL activity (27, 28). Stress induced apoptosis via p53 causes mitochondrial breakdown via caspase 9 (29). Mitochondrial apoptosis is dependent on the ratio of pro and antiapoptotic factors of the Bcl-2 family (30). The Akt signaling pathway promotes antiapoptotic activity and is influenced by estrogen and growth factor-induced cAMP-PKA activity (31, 32).
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