Organoids of the Female Reproductive Tract: Innovative Tools to Study Desired to Unwelcome Processes

Abstract

The pelviperineal organs of the female reproductive tract form an essential cornerstone of human procreation. The system comprises the ectodermal external genitalia, the Müllerian upper-vaginal, cervical, endometrial and oviductal derivatives, and the endodermal ovaries. Each of these organs presents with a unique course of biological development as well as of malignant degeneration. For many decades, various preclinical in vitro models have been employed to study female reproductive organ (patho-)biology, however, facing important shortcomings of limited expandability, loss of representativeness and inadequate translatability to the clinic. The recent emergence of 3D organoid models has propelled the field forward by generating powerful research tools that in vitro replicate healthy as well as diseased human tissues and are amenable to state-of-the-art experimental interventions. Here, we in detail review organoid modeling of the different female reproductive organs from healthy and tumorigenic backgrounds, and project perspectives for both scientists and clinicians.

Keywords: cancer modeling; gynecology; organoids; reproduction; women’s health.

FIGURE 1

Research models for the female reproductive tract. Starting from healthy or diseased tissue from the site of interest within the female reproductive tract (from distal to proximal: vulva, vagina, cervix, endometrium, fallopian tube, ovary and peritoneum/endometriosis), (patho-)physiology can be studied using various preclinical 2D or 3D in vitro, or in vivo models.

FIGURE 2

Applications of organoid model systems. Organoids are stable 3D in vitro representations of the tissue of origin that adequately recapitulate tissue (patho-)biology, and are amenable to manifold basic and (pre-)clinical research applications such as multi-omic scrutiny and gene-editing, host–pathogen interaction mapping and regenerative medicine, biobanking and high-throughput drug testing toward patient-tailored treatments.

FIGURE 3

Epithelial histology of the cervix. Coronal section of the cervix with a detailed visualization of epithelia, from vagina to isthmus: ectocervix, original squamocolumnar junction (SCJ), new SCJ, endocervix.

FIGURE 4

Schematic overview of the endometrium. The cyclically replenished lamina functionalis divides into the superficial stratum compactum and the deeper stratum spongiosum. The persistent lamina basalis lies between the lamina functionalis and the uterine myometrium. Both lamina contain epithelial cells interspersed with varying densities of stromal cells. LE, luminal epithelium, GE, glandular epithelium.

FIGURE 5

Schematic overview of fallopian tube and ovary. (A) The fallopian tube consists of four zones with distinct histological architecture, from distal to proximal: infundibulum with its fimbriae (*), ampulla, isthmus and interstitial/intramural portion. (B) The ovary is divided into a cortical region in which the oocytes/follicles develop and the medulla that contains the larger blood vessels. ***Refers to “Fimbriae”.