Testicles have two main functions: they produce sperm and testosterone. Evidence from clinical and population based surveys suggests an increasing incidence of male reproductive damages. Our long term goal is to study how to let stem cells become testosterone producing cells (Leydig cell), sperm production supporting cells (Sertoli cell) in the testis. In this proposal, we will focus on how to turn stem cells into Leydig cells in the testis. Testis is not closely monitored by immune system. We hypothesize that 1) a proper cells coming from human embryonic stem cells (hESCs) in culture once transplanted into the interstitial space of recipient testes can become Leydig cells in a proper testicular environment; 2) certain hormones promote and stimulate transplanted stem cells turning into Leydig cells in testes. This study has high significance because: 1) we can establish an experimental model to test the plasticity of stem cells (adult or embryonic) in the testis. Utilizing this model we can demonstrate the cellular and molecular mechanisms controlling stem cell function and plasticity in testes. This is crucial to the future use of stem cells in regenerative medicine, as well as in understanding aging, tumor formation, testosterone and sperm production; 2) we can translate the results to clinical studies relevant to the novel treatment of male infertility and testosterone deficiency. The cause of male infertility is either due to the germ cell defect or supporting cells’ dysfunction. In many cases, germ cells are present. The presence of donor-derived healthy cells replacing defective nurturing cells is critical since both Leydig and Sertoli cells support sperm production. Defects in these cells have been believed to contribute to abnormal sperm production. The possibility of beneficial hormonal effects of Leydig cell transplantation independent of their support of sperm production also exits. Since Leydig cells are responsible for testosterone production, stem cell transplantations may replace the need of life-long testosterone supplementation in testicle failure males and aging population. The findings from these studies will have a major impact in the understanding reproductive physiology and recovery from testicular pathology, and also may have the potential for novel future therapies in patients with testicular failure.
Statement of Benefit to California:
California is the biggest state in population in the United States. Infertility affects 15% of couples and 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.