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First-ever in vitro human spermatogenesis

The French startup Kallistem (which stems from research carried out at the Institut de Génomique Fonctionnelle in Lyon) has achieved a world first by obtaining complete human spermatozoa in vitro, using tissue specimens collected from infertile men.

The company, which stems from research carried out at the Institut de Génomique Fonctionnelle in Lyon (CNRS/INRA/Ecole Normale Supérieure de Lyon/Université Claude Bernard Lyon 1), has developed a cell therapy technology that enables the differentiation of germinal stem cells to produce morphologically normal spermatozoa outside the body.

This technology has been the subject of a patent published in June 2015, and was presented at a press conference on 17 September 2015, in Lyon (France).

Several teams throughout the world have been trying for more than fifteen years to achieve in vitro human spermatogenesis, a complex physiological process that lasts 72 days (vs 34 in the mouse). This challenge was taken up by Kallistem's Scientific Director and former INRA senior researcher Philippe Durand, jointly with CNRS senior researcher and company co-founder Marie-Hélène Perrard. The two scientists, who specialize in in vitro spermatogenesis, already knew, by using testicular tissue, how to isolate seminiferous tubules (where spermatozoa are produced), without damaging them. However, confinement of these seminiferous tubules was not sufficiently efficient and stable to allow them to function in vitro throughout the duration of spermatogenesis. A collaboration with Laurent David, Professor at Université Claude Bernard Lyon 1 and a member of the Laboratoire Ingénierie des Matériaux Polymères (CNRS/Université Claude Bernard Lyon1/Insa/UJM), enabled the scientists to develop a containment fluid for seminiferous tubules very similar to in vivo conditions, making integral spermatogenesis possible. To achieve this, the team designed a bioreactor using chitosan, a natural substance present in the cell wall of fungi or produced from chitin, a component in crustacean shells. At the end of 2014, the scientists thus succeeded for the first, time in producing human spermatozoa in vitro. A patent describing the entire system, called "Artistem", was published on 25 June 2015.

This breakthrough opens the way for therapeutic avenues that have been eagerly awaited by clinicians for many years. Indeed, no treatment is currently available to preserve the fertility of young, prepubertal boys undergoing gonadotoxic treatments, such as certain types of chemotherapy. Yet more than 15,000 young cancer patients are affected throughout the world. Nor is there any solution for the 120,000 adult men who suffer from infertility that cannot be treated using existing technologies3. Through the Artistem technique, Kallistem hopes to meet the needs of these two patient groups. From a testicular biopsy in these infertile men, the scientists will be able to obtain spermatozoa in vitro through the maturation of spermatogonial cells4, which are even found in prepubertal boys. The spermatozoa thus obtained will then be used for in vitro fertilization by micro-injection into the oocyte. For the youngest patients, it will be possible to cryopreserve the spermatozoa until they wish to father a child. However, the quality of the spermatozoa thus produced will have to be analyzed before the possibility of such applications can be confirmed. Using rodent models to start with, young rats born from spermatozoa that have developed in vitro will be studied from a physiological and behavioral point of view, notably in order to verify that their organs are normal and that they can reproduce. Then, human gametes will be subjected to biochemical and epigenetic studies. In accordance with the regulations in force, any clinical evaluations will only be performed thereafter.
Published on September 17, 2015