New Penn Vet Research Moves Science Closer to a Solution to Male Infertility

In a breakthrough that could bring scientists closer to a solution to male infertility, a team of Penn Vet researchers have found a way to take cells such as skin or blood cells from the human body, convert them into stem cells, and then coax those into early-stage human sperm cells.

The research, published earlier this month in the journal Cell Stem Cell, represents the most advanced stage yet achieved toward generating functional human sperm in the laboratory.

“If we can make a sperm from a patient’s skin cells or blood cells, that’s going to revolutionize human reproductive medicine,” said Kotaro Sasaki, Richard King Mellon Associate Professor of Biomedical Sciences.

Even with today’s assisted reproductive technologies, many patients remain unable to conceive, particularly those with severely compromised sperm quality or only a very limited number of sperm. “If we could generate functional sperm from a patient’s own non-reproductive cells, it would fundamentally transform the treatment of male infertility,“ said Sasaki.

But how can this be achieved?

Recent advances have made it possible to reprogram virtually any cell from the body into cells resembling those of the early embryo, capable of giving rise to any cell type under the right conditions. These cells, known as induced pluripotent stem cells (iPSCs), have opened the door to regenerative medicine by enabling researchers to generate replacement cells and tissues in the laboratory.

Bridging knowledge gaps to get closer to relief for human male infertility

In principle, iPSCs can also be directed to become sperm or eggs—a concept that has already been demonstrated in mice. “Translating this technology to humans, however, has proven far more challenging,” Sasaki said. “Human germ cell development takes much longer and differs substantially from that of mice. Until very recently, we knew remarkably little about how human sperm-forming cells develop. Those knowledge gaps have been a major barrier to advancing human in vitro gametogenesis – making sperm all the way from iPS cells.

“We believe this is a major step towards completion of in vitro gametogenesis,” Sasaki said. “We are now at the middle or maybe a little bit beyond the middle stage.”

Sasaki and his team mixed their immature cells with non-reproductive cells from  developing mice. The mice cells functioned as ‘nurse cells,’ providing nutrients and support to the developing experimental cells.  

The team transplanted cells into a host supportive of transplanted tissue. The cells began self-organizing into tubular structures similar to those in testicles where sperm are produced. Six months after the transplant, the cells had developed into spermatogonia – early-stage cells that can eventually develop into mature sperm. The Penn Vet team’s cells for the most part stopped at the spermatogonia stage, but their research continues. 

The Penn Vet team also successfully generated early-stage, or precursor, sperm cells from induced pluripotent stem (iPS) cells derived from a non-human primate.

Findings with significance to human infertility sufferers

“This has tremendous translational significance,” Sasaki said. “Ultimately, the function of sperm is best evaluated by its ability to fertilize an egg, but such experiments are ethically and legally impossible in humans. At the same time, sperm development in mice differs substantially from that in humans. A non-human primate model bridges this gap, providing a critical platform to rigorously evaluate the safety, efficacy, and developmental potential of this technology before any future clinical translation.

“We want to take this further down the road,” Sasaki continued.

The Penn Vet researchers acknowledge more work needs to be done before mature sperm can be created in a laboratory. But their current findings represent an additional important contribution to future research – furthering the understanding of how sperm cells are formed.

Understanding how human sperm develops is key to solving many forms of male infertility. According to the World Health Organization, one in six people worldwide experiences infertility, and male factors contribute to about half of all cases.

In some patients, no sperm is produced. More commonly, however, infertility results from defects in how sperm develop.

“Until very recently, we knew remarkably little about how human sperm-forming cells develop or the molecular mechanisms that guide this process,” Sasaki said. “Because these cells develop deep within the fetal and postnatal testes, they are extraordinarily difficult to observe and study.”

“This research provides a powerful new platform to study human sperm development in the laboratory,” Sasaki said. “For the first time, we can systematically uncover the molecular mechanisms that build human sperm and begin to understand why sperm development fails in patients with infertility.”