Organoids of the female reproductive tract

Abstract

Healthy functioning of the female reproductive tract (FRT) depends on balanced and dynamic regulation by hormones during the menstrual cycle, pregnancy and childbirth. The mucosal epithelial lining of different regions of the FRT-ovaries, fallopian tubes, uterus, cervix and vagina-facilitates the selective transport of gametes and successful transfer of the zygote to the uterus where it implants and pregnancy takes place. It also prevents pathogen entry. Recent developments in three-dimensional (3D) organoid systems from the FRT now provide crucial experimental models that recapitulate the cellular heterogeneity and physiological, anatomical and functional properties of the organ in vitro. In this review, we summarise the state of the art on organoids generated from different regions of the FRT. We discuss the potential applications of these powerful in vitro models to study normal physiology, fertility, infections, diseases, drug discovery and personalised medicine.

Keywords: Cancers; Female reproductive tract; Fertility; Infection; Organoids; Pregnancy; Reproductive health.

Fig. 1

Anatomy of the human and mouse FRT. In humans, the FRT consists of ovaries, fallopian tubes, uterus (endometrium and myometrium), cervix (endocervix and ectocervix) and vagina. There are some anatomical differences between the two species, as mice have a bicornuate uterus (uterine horns) and oviducts are much less pronounced in proportion to the rest of the reproductive tract

Fig. 2

The menstrual cycle. The pituitary and ovarian hormones regulating the menstrual cycle and the morphological changes occurring at the ovarian surface epithelium (OSE) and endometrium are depicted. The menstrual phase is divided into menstrual, proliferative and secretory phases. During the proliferative phase, follicle-stimulating hormone (FSH) promotes the growth of ovarian follicles. This results in rising levels of oestrogen (E2) produced by the follicles which then drives the proliferation of the functional layer of the endometrium. Mid-cycle, a peak in E2 results in a surge of luteinizing hormone (LH) and the release of the oocyte (ovulation). This marks the start of the secretory phase, dominated by progesterone (P4), which drives the differentiation (decidualisation) of the endometrium to prepare for implantation. In the absence of implantation, P4 levels drop triggering menstruation, the shedding of the functional layer, to restart the cycle. The basal layer is not shed

Fig. 3

The epithelia of the human FRT. The types of epithelia covering the different regions of the human FRT are illustrated. For each tissue the major cell types are shown, with examples of typical markers they express. Markers with an asterisk are hormonally regulated

Fig. 4

Organoids of normal and diseased tissues of the human FRT. Organoid models derived from normal and pathological tissues are illustrated. The different cell types that are present in the tissue epithelia and the organoids are shown as columnar (non-ciliated), secretory, ciliated, cuboidal and squamous. The organoids recapitulate cellular heterogeneity, genetic signature and key functions of the tissue of origin

Fig. 5

Future applications of organoids of the FRT. Organoids of the FRT are derived from biopsies and can be used to study tissue biology, cell-cell interactions, host-pathogen interactions and disease. Tissue engineering methods combine organoids with other cell types to develop more tissue-like models that include non-epithelial cells. Organoids derived from pathological tissues are useful for drug screening for personalised medicine