Hope for young cancer victims as stem cell transplantation restores functioning sperm in monkeys.

Chemotherapy plays a crucial role in treating many cancers, but unfortunately some chemotherapy has a side effect of destroying the spermatogonial stem cells that are responsible for producing sperm.  Adult men who need to undergo chemotherapy have the option of cryopreserving their sperm in order to give themselves the option of having children in the future, but for young cancer patients who have not yet gone through puberty this is not an option.

Today the BBC news reports on a major advance; scientists at the University of Pittsburgh and Magee-Womens Research Institute have announced that they had taken samples of the spermatogonial  stem cells from 12 adult and 5 prepubescent male macaques and cryopreserved them, administered the macaques with a chemotherapy course that eliminated the remaining spermatogonial stem cells (SSCs), and then thawed and implanted the preserved stem cells after the course of chemotherapy had ended. Nine out of 12 adult monkeys and three out of five prepubescent monkeys were later able to produce sperm again, and additional studies showed that these sperm were capable of fertilising eggs. They were able to show that the sperm were produced by transplanted SSCs and not stem cells that had survived chemotherapy by labelling the transplanted cells with a harmless virus that expressed a Green Fluorescent Protein tag (another interesting application of this Nobel Prize winning technology).

The study by Dr Kyle Orwig and colleagues, published on Thursday in Cell Stem Cell (1), publish work builds on almost 20 years of research, and they discuss how studies in mice and rats initially demonstrating the feasibility of SSC transplantation, while follow-up studies in a range of large animals (including pigs, sheep and monkeys) provided further support for the approach.

The feasibility of this approach is supported by observations in lower animal models that SSCs from donors of all ages, newborn to adult, can regenerate spermatogenesis (Shinohara et al., 2001; Ryu et al., 2003) and that SSCs can be cryopreserved and retain spermatogenic function upon thawing and transplantation (Dobrinski et al., 1999, 2000; Brinster, 2002).

Large animal models are critical for examining the safety and feasibility of experimental therapies before they are translated to the clinic. SSC transplantation has been reported in seven previous large animal studies (Table S1 available online). All of those studies, except for one in the boar (Mikkola et al., 2006), employed irradiation to destroy spermatogenesis and cause infertility. There is a dearth of information on the efficacy of SSC transplantation in chemotherapy-treated large animals, probably due to the significant challenges associated with clinical management of animals treated systemically with highdose chemotherapies that cause severe hematopoietic deficits (Hermann et al., 2007). However, the importance of this experimental paradigm should not be overlooked because high-dose alkylating chemotherapies are used routinely for conditioning prior to hematopoietic stem cell (HSC) transplantation and are associated with high risk of infertility (Wallace et al., 2005”

This study added to this previous research by demonstrating for the first time that it is possible for cryopreserved SSCs to generate functioning sperm in a primate following high dose chemotherapy, and is a major step forward in this field.

Experts in reproductive science have welcomed this study, with Professor Allan Pacey on the University of Sheffield saying:

This report is a very useful step forward and clearly shows that the science of spermatogonial stem cells transplantation might one day work for humans. And, although the authors report relatively low efficiency so far, in the context of someone who does not have any banked sperm to fall back on, these odds are probably very encouraging to make this kind of approach worthwhile.”

It’s certainly true that further research in macaques is needed to ensure that the sperm that result from this technique give rise to healthy offspring, and that cancer cells are not inadvertently transplanted with the SSCs. The second potential problem is already being addressed by Dr. Orwig’s team, who last year demonstrated that where there is a risk that SSCs may be contaminated with cancer cells, it is possible to screen to remove the cancer cells before transplantation. It is also worth noting that such autologous hematopoietic stem cell transfer using cells isolated from a patient’s own bone marrow is a standard part of therapy for some cancers such as lymphoma, and in this week’s paper Dr. Orwig and colleagues highlight the role of animal research in developing this therapy (for which Joseph Murray and Donnall Thomas shared the 1990 Nobel Prize in Physiology or Medicine):

Adult stem cell transplantation for homologous tissue regeneration was first described for primates in the 1950s when bone marrow stem cells were used to reconstitute the hematopoietic systems of monkeys and humans treated with chemotherapy or radiation (Crouch and Overman, 1957; Thomas et al.,1957). Large animals, primarily the dog and monkey, were instrumental for establishing the safety, feasibility, and range of applications for bone marrow transplantation. Today, approximately 50,000 bone marrow or HSC transplant procedures are performed worldwide each year for diseases ranging from cancer to thalassemia, sickle cell anemia, and autoimmune and immune-deficiency disorders (Appelbaum, 2007; Powellet al., 2009).”

Such history is very encouraging, but it is worth paying attention to the final paragraph of the this week’s Cell Stem Cell paper, which notes the great potential of the technique, stresses the need for further development and evaluation, and points out that even when animal studies have played their part further development and study in human trials will be required to realise the full potential of the SSC transfer:

Several promising techniques are in the research pipeline (i.e., SSC transplantation,testicular tissue grafting or xenografting,and in vitro development of gametes) that may allow patients receiving gonadotoxic therapies to preserve their future fertility (Brinster, 2007; Rodriguez-Sosa and Dobrinski, 2009; Sato et al., 2011). SSC transplantation has the unique potential to regenerate spermatogenesis in the autologous environment of the seminiferous tubules, enabling the recipient male to father his own genetic children, possibly through normal coitus. As with hematopoiesis, large animal models that are relevant to human anatomy and physiology will be important for translating the SSC transplantation technique to the human fertility clinic. Considering the successful regeneration of spermatogenesis in the nonhuman primate model reported here and the fact that patients are already preserving testicular tissue and/or cells, clinical translation of the SSC transplantation technique appears imminent. Responsible development of the technology in a clinically relevant nonhuman primate system will help to address issues of safety and feasibility. As with hematopoiesis, the clinical significance and breadth of applications for SSC transplantation will ultimately be established in human patients.”

Dr. Orwig and his colleagues at University of Pittsburgh and Magee-Womens Research Institute for a study that will bring hope to many thousands of cancer patients, and we congratulate them on it, but they also deserve a pat on the back for an excellent paper that shows their appreciation for the long-view of medical research.

1)      Brian P. Hermann, Meena Sukhwani, Felicity Winkler, Julia N. Pascarella, Karen A. Peters, Yi Sheng, Hanna Valli, Mario Rodriguez, Mohamed Ezzelarab, Gina Dargo, Kim Peterson, Keith Masterson, Cathy Ramsey, Thea Ward, Maura Lienesch, Angie Volk, David K. Cooper, Angus W. Thomson, Joseph E. Kiss, Maria Cecilia T. Penedo, Gerald P. Schatten, Shoukhrat Mitalipov, Kyle E. Orwig “Spermatogonial Stem Cell Transplantation into Rhesus Testes Regenerates Spermatogenesis Producing Functional Sperm” Cell Stem Cell – Vol. 11, Issue 5, pp. 715-726 (2012)