In France, between 18% and 24% of couples fail to have a child after one year of regular sexual intercourse without birth control.[1] According to the French Institute for Public Health Surveillance, a significant decrease in sperm count (1.9% per year) was observed in males over the 1989-2005 period. There is a growing interest to model male infertility as a solution to better understand and seek to correct oligozoospermia (sperm count below 15 million/ml) or azoospermia (the total absence of spermatozoa).

"There are few models for studying the differentiation of germ or sexual cells (gametes)," said Lucie Tosca, a partner of the study, researcher and hospital practitioner at the Antoine Béclère hospital in Clamart, France. We are recruiting more and more infertile patients and we have started partnering with CEA to design a genetic model for infertility studies." The researchers used blood cells from an azoosperm patient and administered them a rejuvenation treatment to become stem cells again, i.e. rejuvenate back to the embryonic stage. "This revolutionary technique was invented by Japanese scientist Shinya Yamanaka, the recipient of the 2012 Nobel Prize in Medicine," said Frank Yates, a researcher at the François-Jacob Institute. "It allows us to induce pluripotent stem cells and then differentiate them towards the tissue of interest. This way, one can reprogram any cells of a patient to make them pluripotent, for example blood cells, and induce their differentiation towards germ cells" said Yates' colleague Leïla Maouche Chrétien.

When is differentiation blocked, preventing the germ cell formation? "The model we have created will allow us to answer this question" Maouche Chrétien said. Is it conceivable that researchers could lift this lock to induce sperm production? "Absolutely not," she said, "due the regulatory and ethical aspects of the issue. However, we are able to remove the inhibition in vitro to deepen our understanding of molecular mechanisms while blocking the formation of gametes."

While the discovery by Shinya Yamanaka was the starting point of this model, the techniques of in vitro pluripotent stem cell induction have already evolved significantly. "Currently, no genetic modification of the starting cells is required" Yates explained. "We use the Sendai virus, a non-pathogenic virus from the same family as the measles virus, as a vector to enter the blood cell and express pluripotency proteins. It's a non-invasive technique since this very fragile virus remains in the cell for less than 15 days." Once the cells have been rejuvenated, the next step simply consists of placing them in the presence of an appropriate culture medium to induce the differentiation of interest.

As stated above, this work is not intended to create gametes for infertile patients. However, the understanding of biological locks in the differentiation of stem cells into gametes may one day lead to the development of drugs capable of lifting them.


[1] According to the national perinatal survey carried out in 2003 and the 2007-2008 Epidemiological observatory of fertility in France