Some stem cells, different growth factors, four to six weeks – and of course a lot of expertise is required to create a scaled-down but still realistic and functional copy of a cervix in the laboratory.
A new publication that has now appeared in the magazine Nature protocol shows how the process works in detail. Dr. Cindrilla Chumduri, Head of the Research Group at the Department of Microbiology at the Julius Maximilians University of Würzburg (JMU), is responsible for this. The infection and cancer biologist has for a long time researched the physiological processes in the cervical tissue. She is particularly interested in the conditions under which cancer develops there.
“Until recently, science has lacked a system that well reflects the cellular, physiological and functional properties of the various cell types in the cervix,” says Chumduri. This, she says, has made it difficult to study normal physiology, disease development and infection processes.
With the three-dimensional organoids she has developed, she says, “now opens up new opportunities to study the biology of the cervix, infections and the development of cancer.” New applications in personal medicine, the search for new active substances, interventions on the genome, modeling of diseases: With the help of organoids, researchers were now able to put all this into practice much easier than before.
The cervix has many functions
The cervix is a complicated structure. One of its most important tasks is to enable the passage of sperm into the uterine cavity so that fertilization of the egg can take place. On the other hand, it must protect the female reproductive tract from dangerous invaders such as fungi, viruses and bacteria and from rising infections. In addition, at the end of a pregnancy, it must be possible to widen it considerably so that the fetus can pass through it.
Anatomically, the cervix forms the link between the uterine cavity and the vagina. It consists of the so-called endocervix which is adjacent to the uterus and the ectocervix which protrudes into the vagina. These are bordered by different types of cells: While the endocervix has a columnar epithelium, the ectocervix has a multilayered squamous epithelium. Where the two areas fuse together, they form a transition zone and are particularly susceptible to infection and tissue formation. For example, most cervical cancers originate there.
Stem cells as starting material
For the development of the 3D organoids in the cervix, Cindrilla Chumduri and her team chose adult epithelial stem cells as a starting material. These were taken in biopsies from both endocervix and ectocervix. With the help of unique combinations of growth factors and different culture methods, they were able to recapitulate the natural three-dimensional tissue architecture and composition as well as the functional properties of the original tissue and preserve them for a long time.
In more advanced experiments, the researchers also genetically engineered the stem cells. “We implanted the stem cells with genes from the human papillomavirus HPV, which are responsible for the development of cancer,” says Chumduri. This could potentially solve a mystery that science has been working on for a long time.
Fatal concomitant infections
Because although HPV is known to be the driving force behind the majority of cervical cancers, infection with the virus is not synonymous with malignant tissue neoplasm: Current statistics suggest that about 80 percent of all women will experience an HPV infection during their lifetime. Yet only 1.6 percent of those who develop cervical cancer.
It is now suspected that there are other factors that increase the risk of cervical cancer, such as co-infection with other sexually transmitted pathogens, such as the bacterial pathogen. Chlamydia trachomatis. The genetically modified human ectocervical organoids now allow Chumduri and her team to further investigate the long-term effects of viral infection on cervical epithelium and the contribution of concomitant infections with other pathogens, such as Chlamydia trachomatis.
Great potential for further progress
“Endocervical and ectocervical organoids are ideal, almost physiological 3D epithelial tissues for studying and modeling cervical biology, host-pathogen interactions and disease development,” she is confident. In addition, she says, they are ideal for studying the body’s response to antibiotic-resistant pathogens.
Organoids also make it possible to study the response of the cervical epithelium to hormonal changes and their effects on stem cell regeneration, mucus production and congenital defenses against pathogens. Their long-term viability offers a unique opportunity to take a closer look at chronic or recurrent infections and their impact on host cells, she said.
In any case, Cindrilla Chumduri is convinced: “Overall, the organoid model of the cervix offers great potential for further advances in the study of the biology of the female reproductive organ.”