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Stem cell technique makes first ever viable sperm-in-a-dish.

Infertility affects up to 15% of couples, with roughly one-third of all cases being caused by male infertility.  One major cause of male infertility is the failure of precursor germ cells in the testes to undergo a type of cell division called meiosis to form functional sperm cells. Several studies have reported the successful generation of germ cells from stem cells.

However, the formation of sperm in vitro to produce functional haploid male gametes has not yet been achieved.  Now, researchers at Nanjing Medical University have finally succeeded in creating functioning sperm from embryonic stem cells in the laboratory, which were then injected into egg cells to produce fertile mouse offspring. The team state that their work provides a platform for generating sperm cells that could one day be used to treat male infertility in humans.  The opensource study is published in the journal Cell Stem Cell.

Previous studies show that reproducing germ cell development in vitro has remained a central goal in both reproductive biology and reproductive medicine. Recently, a panel proposed gold standard criteria to prove that the major events of meiosis have taken place in engineered germ cells. For example, researchers must show evidence of the correct nuclear DNA content at specific meiotic stages, normal chromosome number and organization, and the capacity of germ cells to produce viable offspring. Until now, the recapitulation of all of the essential steps of meiosis has remained a major obstacle to the production of functional sperm and egg cells in a dish.  The current study establishes a robust, stepwise approach that recapitulates the formation of functional sperm-like cells in a dish.

The current study developed a stem cell-based method that fully recapitulates meiosis and produces functional sperm-like cells. The lab explain that the first step was to expose mouse embryonic stem cells (ESCs) to a chemical cocktail, which coaxed the ESCs to turn into primordial germ cells. Next, the group mimicked the natural tissue environment of these precursor germ cells by exposing them to testicular cells as well as sex hormones such as testosterone.

Results show that under these biologically relevant conditions, the ESC-derived primordial germ cells underwent complete meiosis, resulting in sperm-like cells with correct nuclear DNA and chromosomal content. To provide final gold-standard proof of meiosis, the researchers injected these sperm-like cells into mouse egg cells and transferred the embryos into female mice. Data findings show that, remarkably, these embryos developed normally and gave rise to healthy, fertile offspring, which gave birth to the next generation.

The team surmise that their method fully complies with the gold standards recently proposed by a consensus panel of reproductive biologists, and think that it holds tremendous promise for treating male infertility.  For the future, the researchers plan to use their platform to examine the molecular mechanisms controlling meiosis and test their approach in other animals such as primates in anticipation of human studies.  They go on to add that if proven to be safe, ethical and effective in humans, their platform could potentially generate fully functional sperm for artificial insemination or in vitro fertilization techniques.

Source: NanJing Medical University

This graphical abstract shows how Zhou et al. generated haploid male gametes from mouse embryonic stem cells that can produce viable and fertile offspring, demonstrating functional reproduction of meiosis in vitro.  Credit: Zhou, Wang, and Yuan et al./Cell Stem Cell 2016.
This graphical abstract shows how Zhou et al. generated haploid male gametes from mouse embryonic stem cells that can produce viable and fertile offspring, demonstrating functional reproduction of meiosis in vitro. Credit: Zhou, Wang, and Yuan et al./Cell Stem Cell 2016.

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