Researchers reporting in the Cell Press journal Cell Reports on May 1st have successfully coaxed stem cells made from the skin cells of infertile men into producing sperm cell precursors. These induced pluripotent stem cells (iPSCs) produced sperm precursors following transplantation into the testes of mice.
The findings help to explain a genetic cause of male infertility and offer a window into basic sperm biology. The approach also holds considerable potential for clinical application, the researchers say.
"Our results are the first to offer an experimental model to study sperm development," said Renee Reijo Pera of the Institute for Stem Cell Biology & Regenerative Medicine and Montana State University. "Therefore, there is potential for applications to cell-based therapies in the clinic, for example, for the generation of higher quality and numbers of sperm in a dish.
"It might even be possible to transplant stem-cell-derived germ cells directly into the testes of men with problems producing sperm," she added. However, getting to that point will require considerable study to ensure the safety and practicality.
Infertility affects 10% to 15% of couples. Moreover, as the researchers note, genetic causes of infertility are surprisingly prevalent among men, most commonly due to the spontaneous loss of key genes on the Y sex chromosome. But the causes at the molecular level have not been well understood.
Reijo Pera said her primary motivation is to understand the fundamental decision early in development that enables the production of sperm cell precursors and ultimately sperm. One way to do that is to study cells lacking genes that are required for sperm production.
The researchers looked to infertile but otherwise normal men with deletions encompassing three Y chromosome azoospermia factor (AZF) regions, which are associated with the production of few or no sperm. They found that iPSCs derived from AZF-deleted cells were compromised in their ability to form sperm in a dish. But when those cells were transplanted into the seminiferous tubules of mice, they produced germ-cell-like cells (though significantly fewer than iPSCs derived from people without the AZF deletion do).
The findings show that the developmental defect in men with these deletions occurs relatively late in the differentiation of sperm cells. Reijo Pera says the findings and approach also may yield new strategies in the diagnosis and assistance of those with genetic or secondary infertility, just as they may be used to treat degenerative or age-related diseases.
"Our studies suggest that the use of stem cells can serve as a starting material for diagnosing germ cell defects and potentially generating germ cells," she said. "This approach has great potential for treatment of individuals who have genetic/idiopathic causes for sperm loss or for cancer survivors who have lost sperm production due to gonadotoxic treatments."
Cell Reports, Ramathal et al.: "Fate of iPSCs Derived from Azoospermic and Fertile Men Following Xenotransplantation to Murine Seminiferous Tubules."