Men’s health and quality of life are largely dependent on fully functional testes. Testes have two main functions: they produce sperm and the male hormone testosterone. Evidence from clinical and population based surveys suggests an increasing incidence of male reproductive problems. About 15% of couples are infertile. Male infertility and low testosterone levels due to abnormal function of the testis are caused either by defects in the germ cells, cells that support maturation of sperm or cells that made testosterone. Stem cell therapy provides new opportunities to replace and replenish damaged and dysfunctional testicular cells. Studies have demonstrated that transplantation of stem cells of testis origin into dysfunctional recipient testes can restore the capability to regenerate sperm and produce more testosterone. Because of the unavailability of stem cells from testes and ethical challenges of genetic paternity for future clinical applications, our proposed studies will use bone marrow stem cells as a more feasible source for replacement of dysfunctional testicular cells. Previous studies including a study from our lab have demonstrated that bone marrow stem cells have potential capabilities to replenish germ cells, supporting cells and testosterone producing cells in dysfunctional testes. In the proposed studies, we will first isolate bone marrow stem cells from donor animals and increase the population of stem cells in culture before transplanting these enriched stem cells into recipient testes of various animal models for male infertility and men with low testosterone levels. In addition, we will test the effect of different testis environments, hormones, growth factors on stem cell plasticity. This study is important because: 1) we can use this model to study the cellular and molecular mechanisms controlling stem cell function and plasticity within the microenvironment of the testis. This is crucial to the future use of stem cells in regenerative medicine, sperm production, male aging, and testicular tumor formation; 2) we can explore the potential of novel stem cell therapy for male Infertility and low testosterone. With diminished ethical issue by harvesting the patient’s own bone marrow stem cell and transplanting into their own testes for treatment of male testicular failure, we can more easily translate our findings into clinical studies; 3)This method could also be important for re-establishing genetic paternity, with or without assisted fertilization technology, in the setting of patients with cancer (not involving the bone marrow) following chemotherapy; 4) we can develop stem cell therapy to replace the need of life-long testosterone supplementation in testicle failure males and aging population. Thus, our study will have major consequences for the understanding of reproductive biology, pathology and clinical implications for novel future therapies in men with congenital and/or acquired primary testicular failure.
Statement of Benefit to California:
Infertility affects 15% of couples in attempting their first pregnancy and of these 30% is due to male factor infertility. Evidence from clinical and population based surveys suggests an increasing incidence of male reproductive problems. In addition to the mentally and physically suffering in men, testicle failure sometimes contributes to social instability of the family. Our long term goal is to develop regenerative strategies to maintain, improve and rescue testicular functions through the stem cell research. In addition, understanding the cellular and molecular mechanisms controlling stem cell function and plasticity is crucial to the future use of stem cells in regenerative medicine, as well as in understanding aging, tumor formation, testosterone secretion and sperm production. Techniques generated from this study will contribute to biotech industrial development in California.