Pig oocyte surrounded by granulosa cells. Fluorescence microscopy, colored with DAPI.

A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete (called an oocyte or egg) in the ovary of mammals.

Structure and function

In the primordial ovarian follicle, and later in follicle development (folliculogenesis), granulosa cells advance to form a multilayered cumulus oophorus surrounding the oocyte in the preovulatory or antral (or Graafian) follicle.

The major functions of granulosa cells include the production of sex steroids, as well as myriad growth factors thought to interact with the oocyte during its development. The sex steroid production begins with follicle-stimulating hormone (FSH) from the anterior pituitary, stimulating granulosa cells to convert androgens (coming from the thecal cells) to estradiol by aromatase during the follicular phase of the menstrual cycle.[1] However, after ovulation the granulosa cells turn into granulosa lutein cells that produce progesterone. The progesterone may maintain a potential pregnancy and causes production of a thick cervical mucus that inhibits sperm entry into the uterus.

Embryology of ovarian granulosa cells

In the development of the urinary and reproductive organs, the oogonia become invaginated in the gonadal ridge.

The embryological origin of granulosa cells remains controversial. In the 1970s, evidence emerged that the first cells to make contact with the oogonia were of mesonephric origin. It was suggested that mesonephric cells already closely associated with the oogonia proliferated throughout development to form the granulosa cell layer.[2][3][4] Recently, this hypothesis has been challenged with some thorough histology. Sawyer et al. hypothesized that in sheep most of the granulosa cells develop from cells of the mesothelium (i.e., epithelial cells from the presumptive surface epithelium of the ovary).[5] In 2013, it was proposed that both granulosa cells and the ovarian surface epithelial cells are instead derived from a precursor cell called gonadal-ridge epithelial-like cell. [6]

Granulosa cell types

Cumulus cells (CC) vs mural granulosa cells (MGC)

Cumulus cells surround the oocyte. They provide nutrients to the oocyte and influence the development of the oocyte in a paracrine fashion. Mural granulosa cells line the follicular wall and surround the fluid-filled antrum. The oocyte secretes factors that determine the functional differences between CCs and MGGs. CCs primarily support growth and development of the oocyte whereas MGCs primarily serve an endocrine function and support the growth of the follicle. Cumulus cells aid in oocyte development and show higher expression of SLC38A3, a transporter for amino acids, and Aldoa, Eno1, Ldh1, Pfkp, Pkm2, and Tpi1, enzymes responsible for glycolysis.[7] MGCs are more steroidogenically active and have higher levels of mRNA expression of steroidogenic enzymes such as cytochrome P450.[8] MGCs produce an increasing amount of estrogen which leads to the LH surge.[9] Following the LH surge, cumulus cells undergo cumulus expansion, in which they proliferate at a ten-fold higher rate than MGCs in response to FSH.[10] During expansion CCs also produce a mucified matrix required for ovulation.[11]

Cell culture

Cell culture of granulosa cells can be performed in vitro. Plating density (number of cells per volume of culture medium) plays a critical role for the differentiation. A lower plating density makes granulosa cells exhibit estrogen production, while a higher plating density makes them appear as progesterone producing theca lutein cells.[12]

Ovarian aging

In the female rhesus monkey, DNA double-strand breaks increase in granulosa cells with age, and the ability to repair such DNA breaks declines with age.[13] These changes at the DNA level in granulosa cells may contribute to ovarian aging.[13]

Additional images

Section of vesicular ovarian follicle of a cat. X 50. Membrana granulosa labeled at upper left.

See also

References

  1. ↑ Garzo, V. G.; Dorrington, J. H. (1984). "Aromatase activity in human granulosa cells during follicular development and the modulation by follicle-stimulating hormone and insulin". American Journal of Obstetrics and Gynecology. 148 (5): 657–662. doi:10.1016/0002-9378(84)90769-5. PMID 6422764.
  2. ↑ Satoh M (1991). "Histogenesis and organogenesis of the gonad in human embryos". J Anat. 177: 85–107. PMC 1260417. PMID 1769902.
  3. ↑ Upadhyay S, Zamboni L (1982). "Preliminary observations on the role of the mesonephros in the development of the adrenal cortex". Anat Rec. 202 (1): 105–111. doi:10.1002/ar.1092020112. PMID 7059014. S2CID 40498196.
  4. ↑ Zamboni, L.; Bezard, J.; Mauleon, P. (1979). "The role of the mesonephros in the development of the sheep fetal ovary". Annales de Biologie Animale, Biochimie, et Biophysique. 19 (4B): 1153–78. doi:10.1051/rnd:19790801.
  5. ↑ Sawyer H, Smith P, Heath D, Juengel J, Wakefield S, McNatty K (2002). "Formation of ovarian follicles during fetal development in sheep". Biol Reprod. 66 (4): 1134–50. doi:10.1095/biolreprod66.4.1134. PMID 11906935. S2CID 2271384.
  6. ↑ Hummitzsch, K; Irving-Rodgers, HF; Hatzirodos, N; Bonner, W; Sabatier, L; Reinhardt, DP; Sado, Y; Ninomiya, Y; Wilhelm, D; Rodgers, RJ (2013). "A new model of development of the mammalian ovary and follicles". PLOS ONE. 8 (2): e55578. Bibcode:2013PLoSO...855578H. doi:10.1371/journal.pone.0055578. PMC 3567121. PMID 23409002.
  7. ↑ Eppig, J. J., Pendola, F. L., Wigglesworth, K., & Pendola, J. K. (2005). Mouse oocytes regulate metabolic cooperativity between granulosa cells and oocytes: amino acid transport. Biology of reproduction, 73(2), 351-357.
  8. ↑ Li, R., Norman, R. J., Armstrong, D. T., & Gilchrist, R. B. (2000). Oocyte-secreted factor (s) determine functional differences between bovine mural granulosa cells and cumulus cells. Biology of reproduction, 63(3), 839-845.
  9. ↑ Diaz, F. J., Wigglesworth, K., & Eppig, J. J. (2007). Oocytes determine cumulus cell lineage in mouse ovarian follicles. Journal of cell science, 120(8), 1330-1340.
  10. ↑ Khamsi, F., & Roberge, S. (2001). Granulosa cells of the cumulus oophorus are different from mural granulosa cells in their response to gonadotrophins and IGF-I. Journal of endocrinology, 170(3), 565-574.
  11. ↑ Chen, L., Russell, P. T., & Larsen, W. J. (1993). Functional significance of cumulus expansion in the mouse: roles for the preovulatory synthesis of hyaluronic acid within the cumulus mass. Molecular reproduction and development, 34(1), 87-93.
  12. ↑ Portela VM, Zamberlam G, Price CA (April 2010). "Cell plating density alters the ratio of estrogenic to progestagenic enzyme gene expression in cultured granulosa cells". Fertil. Steril. 93 (6): 2050–5. doi:10.1016/j.fertnstert.2009.01.151. PMID 19324349.
  13. 1 2 Zhang D, Zhang X, Zeng M, Yuan J, Liu M, Yin Y, Wu X, Keefe DL, Liu L. Increased DNA damage and repair deficiency in granulosa cells are associated with ovarian aging in rhesus monkey. J Assist Reprod Genet. 2015 Jul;32(7):1069-78. doi: 10.1007/s10815-015-0483-5. Epub 2015 May 10. PMID: 25957622; PMCID: PMC4531862
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