Model systems help scientists to investigate how cells, tissues and organs work. Such laboratory models should be as similar to their natural counterparts as possible. Researchers from the Max Planck Institute for Infection Biology in Berlin have now grown the innermost layer of human fallopian tubes – a mucous membrane epithelium with folds and projections – in the lab. Stem cells develop not only into the cell types that occur in the mucosal layer, but features of the organ as a whole, for example its characteristic architecture. Using their laboratory model, the researchers have discovered two signalling pathways that are essential for continuous growth. They also concluded that the mucosa of the fallopian tubes possesses its own stem cells, resulting in continuous renewal. Based on their findings, and thanks to their newfound ability to study artificial fallopian tubes in the lab, the scientists hope to shed light on the course of infections and the development of cancer progenitors in the fallopian tubes.
The fallopian tubes – also called oviducts − are part of the female reproductive system. The tubes, around 10 to 15 cm in length, connect the ovaries to the uterus and facilitate transport of the fertilized egg to the uterus. They are therefore essential for successful reproduction.
“However, the fallopian tubes can be chronically infected by bacteria,” explains Thomas F. Meyer, head of the study and Director at the Max Planck Institute for Infection Biology. Such infections can lead to blockage of the fallopian tubes and in severe cases infertility. “Recent findings from cancer research also indicate that transformed cells from the fallopian tubes can spread to the ovaries,” Meyer adds. This could give rise to ovarian carcinoma, one of the most dangerous forms of gynaecological cancer.
Doctors have only limited means to examine the insides of their female patients’ fallopian tubes. As a result, diseases of the fallopian tubes are often not diagnosed until they reach an advanced stage – and then it is often too late for successful treatment. It is also difficult to produce oviduct-like conditions in the lab. The inner mucosal layer of the fallopian tubes, the epithelial layer, is of special interest in this respect, as it is often the site at which infections and cancer originate.
Meyer’s team, working in cooperation with clinicians in the Gynaecology Department of Charité Hospital in Berlin, have now devised a new method to grow the inner cellular layer in the lab. They removed epithelial cells with potential stem cell properties from fallopian tube samples provided by donors and then cultivated them under specific environmental conditions. A very small number of cells developed into hollow spheres known as organoids, which consist of many thousands of cells. “That happened without any additional instruction whatsoever,” says Dr. Mirjana Kessler, the first author of the study. “The entire blueprint of the fallopian tube must therefore be stored in the epithelial cells.”
The researchers found that the anatomy, structure and biochemical processes in the organoids were very similar to those of real fallopian tubes. “The artificial models consist of stem cells, as well as ciliated cells and secretory cells, all of which are arranged in the same way as in natural fallopian tubes,” according to Kessler. Moreover, the artificial fallopian tubes respond to the addition of hormones to the nutrient solution. These and other analogous characteristics show that the initial cells used have the potential to mature into specialised cells.
The scientists are also studying how the artificial mucosa develops. They have discovered that two signalling pathways, known as Notch and Wnt, lead to the development of an organoid that closely resembles a real fallopian tube and allow the cells to respond to external signals. Both pathways play a key role, particularly during embryonic tissue development. Depending on the stage of development, they inhibit or stimulate further changes in the cells.
Despite having been cultivated in the lab for over a year, the organoids have not shown any appreciable changes. “That is a huge advantage,” explains Kessler, “previously available models could only keep fallopian tube epithelial cells alive for a few days. The ability to maintain the tissue-specific stem cells in culture, so they continuously replenish the cells means that these organoids can serve as research objects for much longer.”
Beyond these preliminary results, the Berlin-based scientists hope to gain fresh insights into the underlying mechanisms of reproduction and cancer development in the fallopian tubes. “With the help of our model we can now focus on determining whether cancer can be triggered by infections of the human fallopian tubes,” Meyer concludes.