Stem Cell Transplants Restore Fertility in Monkeys
Injections of banked sperm-making stem cells can restore fertility to male non-human primates. This work comes from stem cell researchers at the University of Pittsburgh School of Medicine and the Magee-Womens Research Institute and was published in the journal Cell Stem Cell.
This is a remarkable finding because some men or boys must undergo cancer treatment before they have their families. Since cancer drugs destroy dividing cells and do not discriminate between normal cells and cancer cells, the stem cells that make sperm tend to take a serious beating during chemotherapy. The cancer might be destroyed, but the patient will be rendered sterile.
The senior investigator for this work, Kyle Orwig, associate professor in the Department of Obstetrics, Gynecology and Reproductive Medicine at the University of Pittsburgh School of Medicine said: “Men can bank sperm before they have cancer treatment if they hope to have biological children later in their lives,” he says. “But that is not an option for young boys who haven’t gone through puberty, can’t provide a sperm sample, and are many years away from thinking about having babies.”
Young boys that have yet to experience puberty do not yet make any sperm, but they have a modicum of spermatogonial stem cells in their testes that are waiting in the wings to produce sperm during puberty. During puberty, neurons in a part of the brain called the hypothalamus release a 10-amino acid peptide called “gonadotropin releasing hormone” (GnRH). Because these neurons release their GnRH into blood vessels that feed the pituitary gland, just below the hypothalamus, it flows directly to the pituitary.
GnRH stimulates the anterior lobe of the pituitary to release two trophic hormones: follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are collectively known as gonadotropins. FSH initiates sperm cell production in the tubules within the testes and LH stimulates the synthesis of the steroid hormone testosterone, which is necessary for sperm maturation.
Orwig and his colleagues wanted to determine if it is possible to restore fertility by freezing and banking these spermatogonial stem cells and then reintroducing them back into the testes after the completion of chemotherapy. Orwig and others took biopsies from the testes of young, adult male macaque monkeys that had yet to experience puberty. This tissue was cryopreserved in small samples. Then the monkeys were treated with chemotherapy agents that are known to reduce fertility.
A few months after chemotherapy treatment, Orwig and his colleagues transplanted each monkey’s own spermatogonial stem cells into their own testes by means of ultrasound-guided surgery. Nine of twelve adult animals showed restoration of sperm production and three of five very young animals that had not yet experienced puberty demonstrated an ability to make functional sperm after they reached maturity.
In a second experiment, spermatogonial stem cells from unrelated monkeys were transplanted into infertile animals. These transplanted cells generated sperm that had the DNA fingerprint of the donor. Because the testes contain a barrier to the immune system that prevents access of the sperm to the immune system, the implanted tissue could survive without being attacked by the immune system. This is a problem is males who have immune responses to sperm. For example, men who have had a vasectomy or make homosexuals have immune responses to human sperm. Laboratory tests showed that sperm from transplant recipients successfully fertilized 81 eggs that lead to embryos that developed normally. Donor parentage was confirmed in these embryos.
“This study demonstrates that spermatogonial stem cells from higher primates can be frozen and thawed without losing their activity, and that they can be transplanted to produce functional sperm that are able to fertilize eggs and give rise to early embryos,” Orwig says.
Several centers in the U.S. and elsewhere are already banking testicular tissue for young male cancer patients. This is in future anticipation that new stem cell-based therapies will be developed that will help them achieve pregnancy and have their own biological children. Thus this proof-of-principle experiment has generated no small degree of excitement for clinicians and patients who have compromised fertility.
According to Orwig, “These patients and their families are the pioneers that inspire our research and help drive the development of new medical breakthroughs.” He continued: “Many questions remain to be answered,” Orwig notes. “Should we re-introduce the spermatogonial cells as soon as treatment is over, or wait until the patient is considered cured of his disease, or when he is ready to start a family? How do we eliminate the risk of cancer recurrence if we give back untreated cells that might include cancer cells? These are issues we still must work through, but this study does show us the concept is feasible.”