Stem cell-based therapy provides new opportunities to replace and replenish damaged and dysfunctional testicular cells. Studies in rodent 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 from your own 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 mice and increase the population of stem cells in culture, and then we will transplant these enriched and/or reprogrammed stem cells into recipient testes of various animal models for men with infertility and/or low testosterone levels. We will induce bone marrow stem cells differentiation toward testicle specific cells in culture before transplantation to increase their transformation efficiency in recipient testes. In addition, we will test the effect of different testis environments, hormones, growth factors on stem cell plasticity. Through proposed studies, we will 1) develop experiment model to determine 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 and provides insight to understanding reproductive aging, testicular tumor formation and spermatogenesis; 2) provide supportive data leading to the development of cell-based stem cell therapy for men with infertility and/or low testosterone levels. Thus, our study will have major consequences for the understanding of reproductive biology, pathology and clinical implications for novel future therapies in men with primary testicular failure.
Statement of Benefit to California:
Male infertility and men with low testosterone levels are common and important clinical conditions affecting male reproductive health. Evidence from clinical and population based surveys suggests an increasing incidence of male reproductive defects. 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 be benefit for Californian and contribute to biotech industrial development in California.