With male infertility rates rising globally, researchers have shown for the first time that functional sperm cells can be made in a dish using primate embryonic stem cells.
Male infertility is a global health issue. Currently, ~12% of men in the United States are subfertile or infertile. There are several causes of male infertility including genetic defects, environmental toxicants, injury or medical treatments (e.g., chemotherapy). Unfortunately, as there is no cure, men who are unable to produce gametes are unable to father children.
Recent work has demonstrated that human pluripotent stem cells (hPSCs), including human embryonic (hESCs) and induced pluripotent stem cells (hiPSCs) can differentiate into germ cell lineages. These studies have shown the production of spermatogonia-like cells, primary and secondary spermatocyte-like cells and haploid spermatid-like cells. Unfortunately, due to ethical and legal concerns, researchers have not been able to assess ‘gold standards’ for producing functional gametes that could fertilise an oocyte.
In addition, previous work has also demonstrated the ability to produce live offspring in rodents from sperm cells. These were generated by testicular grafts with primordial germ cells derived from mouse embryonic stem cells. However, there are distinct biological and kinetic differences between rodents and humans which could prevent these results from being translated.
Deriving functional gametes from pluripotent stem cells
In a recent study, published in Fertility and Sterility Science, researchers tested whether functional gametes could be derived in vitro from pluripotent stem cells using a non-human primate – the rhesus macaque. Rhesus macaques share similar biological mechanisms to humans for spermatogenesis, fertilisation, early embryo and foetal development. They are also more kinetically similar to humans than rodents.
The team specifically differentiated the rhesus macaque’s non-human primate embryonic stem cells (nhpESCs) into advanced male germ cell lineages using a modified serum-free spermatogonial stem cell culture medium. The researchers then assessed the ability of derived spermatid-like cells to fertilise rhesus macaque oocytes.
They found that nhpESCs could be differentiated into advanced germ cell lineages. This included haploid round spermatid-like cells (rSLCs). These cells were able to undergo DNA decondensation and pronucleus formation when injected into rhesus macaque mature oocytes. After artificial activation, these oocytes underwent embryonic division. In total, ~12% of the fertilised oocytes developed successfully into expanded blastocysts.
Implications and future work
This work has demonstrated, for the first time, that functional spermatid-like cells can be derived in vitro from primate pluripotent stem cells. It is also a major step toward future clinical therapies that may help address the rising rates of male infertility.
Lead researcher, Charles Easley, said:
“This is a major breakthrough towards producing stem cell-based therapies to treat male infertility in cases where the men do not produce any viable sperm cells.”
The team plan to next implant these embryos into a surrogate rhesus macaque to examine whether these embryos could produce a healthy baby. If successful, the researchers also plan to carry out the same process using spermatid-like cells derived from macaque skin cells.
Image credit: canva