Where are the Theca Cells From: The Mechanism of Theca Cells Derivation and Differentiation
The ovary is a vital female reproductive organ that undergoes continuous and dynamic changes throughout development. Follicles, the basic units of ovarian structure and function, are primarily composed of three cell types: oocytes, granulosa cells, and theca cells. Theca cells first appear in secondary follicles, which have two or more layers of granulosa cells, although true theca layers have not yet formed at this stage. In antral follicles, complete theca layers surrounding granulosa cells consist mainly of theca cells, vascular structures, and immune cells. The theca interna is composed of steroidogenic theca cells, vascular endothelial cells, and immune cells, while the theca externa primarily contains fibroblast-like cells. Theca layers in antral follicles synthesize hormones and secretory factors such as androgens and bone morphogenetic proteins (BMPs), transport nutrients to granulosa cells, cumulus cells, and oocytes through vascular structures, and provide structural support for spherical follicles. After ovulation, theca cells invade granulosa cell layers along with vascular and immune cells to form the corpus luteum. However, the more common fate of theca cells is atresia, during which they undergo apoptosis early or late depending on the stage of folliculogenesis.
Despite their critical role in folliculogenesis, theca cells have long been neglected in research. Many questions remain unanswered, such as the origin of theca cells, the role of fibroblast-like cells in the theca externa during ovulation, the possibility of culturing theca cell lines in vitro, and the impact of vascular and immune factors in theca layers on the follicular ecosystem. This article focuses on the origin of theca cells and the factors involved in their recruitment and differentiation, aiming to provide a comprehensive understanding of theca cells’ life cycle.
The formation of theca layers is a crucial physiological event in early folliculogenesis. Two main theories address the origin of theca cells. The first theory suggests that theca cells originate from stem cells. In 2007, researchers isolated putative theca cells from the ovaries of newborn mice after luteinizing hormone (LH)-induced differentiation. These cells, similar to fibroblasts in morphology, could be induced to differentiate into steroidogenic cells and were regarded as theca stem cells due to their ability to self-renew and differentiate both in vivo and in vitro. However, the purity of these cells was uncertain, and no further studies have reinforced this theory. The second, more widely accepted theory posits that theca cells originate from progenitor cells in embryos. This theory is based on a study that identified two theca cell progenitors using a Gli+ cell lineage tracing model in mouse embryogenesis. These progenitors are Wilms tumor 1-positive (Wt1+) cells from the gonadal primordium and Gli1+ cells that migrate from the mesonephros. Transcriptome comparisons of these progenitors revealed that genes associated with steroidogenesis, such as steroidogenic acute regulatory (Star), cytochrome P450 17A1 (Cyp17a1), cytochrome P450 11A1 (Cyp11a1), and LH/choriogonadotropin receptor (Lhcgr), were enriched in mesonephros-derived Gli1+ cells. In contrast, estrogen receptor 1 (Esr1), Wt1, and genes involved in cell growth and proliferation were more enriched in ovary-derived Gli1+ cells. This pattern of origination and differentiation through two progenitors is similar to that of Leydig cells in the testes.
The differentiation of theca cells is regulated by the local follicular environment. Granulosa-theca cell co-culture experiments have shown that the presence of granulosa cells stimulates theca cell proliferation and increases steroid hormone secretion. Granulosa cells also play a role in the differentiation and acquisition of LH responsiveness in stromal cells of the ovarian cortex. Additionally, oocytes influence the formation of theca layers. The proliferation, differentiation, and steroidogenesis of theca cells are modulated by factors synthesized by oocytes and granulosa cells. Hormones from other parts of the body may also affect theca cell recruitment, although research on this topic is limited.
The hedgehog (Hh) pathway is believed to play a significant role in regulating the origin of theca cells. The Hh pathway, first identified in Drosophila, is crucial for regulating sexual differentiation, normal organ development, and pathological processes such as tumorigenesis. In mammals, the Hh pathway consists of three ligands: Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh). Dhh and Ihh are mainly produced by granulosa cells, while PTCH1/2, huntingtin-interacting protein 1, and Gli1 are primarily located in adjacent theca cells. The Hh pathway regulates theca cell formation and differentiation, as evidenced by the decreased expression of steroidogenic genes and inhibited theca layer formation in mice with specific knockout of Dhh or Ihh in granulosa cells. The expression of Dhh and Ihh in granulosa cells is regulated by oocyte-secreted growth differentiation factor 9 (GDF-9), forming an axis composed of GDF-9 (oocytes), Dhh/Ihh (granulosa cells), and PTCH (theca cells) that plays a crucial role in theca layer formation.
The transforming growth factor-beta (TGF-β) superfamily, particularly GDF-9 and BMP-15, also plays a significant role in regulating theca cell function. GDF-9, essential for oocyte maturation, ovulation, follicular cell proliferation, and steroid hormone synthesis, promotes theca cell proliferation and steroidogenesis. GDF-9’s effect on theca cells is mediated through the GDF-9-Dhh/Ihh-PTCH signaling axis. BMP-15, another oocyte-derived factor, regulates follicular cell recruitment, development, ovulation, atresia, and steroid hormone secretion. BMP-4 and BMP-7, expressed in the theca interna and externa, regulate folliculogenesis and steroidogenesis, with BMP-7 promoting folliculogenesis progression before the antral follicle stage and BMP-4 promoting the transformation from primordial to primary follicles.
Kit ligand (KL), a granulosa cell-derived factor, is involved in the regulation of theca cell function. KL promotes the proliferation and recruitment of specific undifferentiated stromal cells to surround primary follicles and increases androgen production in theca cells. The c-Kit system, including KL and its receptor c-Kit, is expressed in theca cells of many vertebrates and plays a role in theca cell recruitment, proliferation, and steroidogenesis. Keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), derived from theca cells, modulate KL expression in granulosa cells, creating a positive feedback loop between granulosa and theca cells.
Insulin-like growth factor 1 (IGF-1), produced by granulosa cells, stimulates theca cell proliferation and steroidogenesis in a paracrine manner. IGF-1 promotes the differentiation of theca cells and increases the number of gap junctions between theca-granulosa cells and granulosa cell-oocytes, facilitating signal communication between follicular cell components. Growth hormone (GH), which stimulates IGF-1 synthesis in the liver, indirectly regulates theca cell proliferation and differentiation. GH also impacts the effect of gonadotropins on follicular somatic cells, increasing the density of follicle-stimulating hormone and LH receptors in human granulosa cells.
Other factors, such as basic fibroblast growth factor (bFGF), retinoic acid, and GATA6, are also involved in theca cell function. bFGF promotes folliculogenesis and the growth and steroidogenesis of theca and granulosa cells. Retinoic acid and GATA6 increase the expression of CYP17A1, promoting androgen production. In polycystic ovary syndrome (PCOS), theca cells exhibit increased expression of GATA6, retinoic acid synthase, aldehyde dehydrogenase 6 (ALDH6), and retinol dehydrogenase 2 (RDH2), contributing to hyperandrogenemia. The Wnt signaling pathway, inhibited in PCOS theca cells, may also play a role in folliculogenesis and theca layer development.
In conclusion, folliculogenesis is a dynamic process involving oocytes and somatic cells, with theca cells playing an essential role, particularly in antral follicles and later stages. The formation of theca layers involves the recruitment and growth of theca cells and the development of vascular structures. A complex regulatory system composed of various factors derived from oocytes, granulosa cells, and signaling pathways in theca cells governs the recruitment and differentiation of theca cells. Understanding the derivation, differentiation, and function of theca cells is crucial for elucidating the mechanisms of follicular formation and development, improving follicle and embryo quality, and treating clinical conditions such as PCOS.
doi.org/10.1097/CM9.0000000000000850
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