Associate Professor, Department of Obstetrics and Gynecology
Biology and clinical application of male germline stem cells.
If a 6-year old boy must take cancer chemotherapy and will likely become infertile, no techniques are currently available that help him have genetic children in the future. For adults, sperm-banking is the option but it is not an option for prepubertal and adolescent boys. This is an important quality of life issue to the patient himself, but also to the patient’s family and his future partner. I investigate sperm-producing stem cells (spermatogonial stem cells, SSCs), which exist from the time of birth and throughout life, and critically, these cells provide an irreplaceable resource to preserve fertility of boys and men at any age. We expect that SSCs can be harvested from a patient before therapy, and following cryopreservation, transplanted back to the patient, resulting in the production of his own sperm. This scheme has already been realized in animal models. Why not with humans? This is our research goal.
Our current research focuses on three critical issues in SSC research.
- To generate a fate map of SSC commitment in mice and humans. We ask, what are the steps of SSCs commitment to differentiation until they lose their stemness, and what occurs during the process? Through these efforts, we eventually want to "see" SSCs with our own eyes, which no one has been able to do since the first SSC concept proposed in 1885. Over several years, we have accumulated the abundance of important data using flow cytometry and the SSC transplantation assay. We can now purify mouse SSCs to the level that has not been reported before without using a transgenic marker gene or modifying cells in any way. We are currently analyzing single cell transcriptome data and hope to report our finding in the near future. A glimpse of this research activity can be seen on a YouTube video at “https://www.youtube.com/watch?v=OYQPpoat6tg”.
- To develop novel technologies to increase the SSC homing efficiency after transplantation. We collaborate with developmental biologists, clinical andrologists, and chemical engineers at McGill and have been designing and producing novel compounds in order to allow for more SSCs to engraft and regenerate spermatogenesis after transplantation. We envision that our new approach should make the restoration of male fertility after SSC transplantation more efficient and effective. The animal testing phase is near completion and we plan to move on to preclinical human studies.
- To apply human SSCs to clinical settings, including developing a reliable and reproducible human SSC culture to expand them and assess their genetic and epigenetic integrity during the culture period. We also believe that our first research aim (fate map) is a very essential research process to realize human SSC propagation in vitro, which has not been successful. For this aim, we collaborate with clinicians at the MUHC and researchers at the University of Pittsburgh
The Nagano lab constantly looks for new lab members, the enthusiastic people who are full of curiosity for nature, biology, and the mystery of creatures with whom we cannot share a language. At the level of postdoc, grad students, research assistant, or lab technician. If you are interested, please email me at makoto.nagano [at] mcgill.ca.
Dr. Makoto Nagano graduated from the Tokyo University of Agriculture and Technology (Japan) with M.Sc. (Dr. Shuji Sasamoto, supervisor) and obtained veterinary license from the Ministry of Agriculture, Forestry, and Fishery of the Government of Japan. He received his PhD at the University of Paris XI (France), working at the Necker Sick Children’s Hospital in Paris. His supervisor was Dr. Paul A. Kelly. He conducted his postdoctoral research at the University of Pennsylvania under the supervision of Dr. Ralph L. Brinster. Since 1995, Dr. Nagano's research has been focusing on biology and clinical applications of stem cells in the male germ line, called spermatogonial stem cells (SSCs). He has significantly contributed to the development of the SSC research field in a broad range of areas as follows:
- Established spermatogonial transplantation as the unequivocal and quantitative assay of SSCs.
- Established xenogeneic spermatogonial transplantation for non-human primate and human SSCs.
- Reported the first successful culture of SSCs in vitro.
- Demonstrated the feasibility of genetic modification of SSCs using retro- and lentiviral vectors.
- Reported the first success of transgenesis through SSCs; transmitting a gene to future generations after transplantation of genetically modified SSCs in mice.
- Determined the absolute number of SSCs in the testis of adult and immature mice.
- Determined the homing efficiency of SSCs after transplantation.
- Demonstrated that one SSC can regenerate complete spermatogenesis (clonal regeneration).
- Established an in vitro SSC assay that reduced the assay period from 2 months with SSC transplantation to 1 week with this in vitro assay.
- Demonstrated that both SSCs and their stem cell niche suffer from aging.
- Revealed the kinetics of SSC recovery and male fertility restoration after genotoxic damage.
- Demonstrated the contribution of non-canonical Wnt signaling to SSC fate decision control and the effect of canonical Wnt signaling on committed progenitors.
In addition, in 2013, Dr. Nagano proposed a novel concept of SSC fate control; SSC fate is likely fine-tuned via communications with their daughter germ cells rather than being induced by somatic niches (Curr Top Dev Biol, 2013, Vol. 102, pp. 61-96. Academic Press).
Research at the Nagano lab has been continuously supported by the CIHR since 2001.