Although the potential of embryonic stem cell-based therapy to cure disease is tremendous, its progress has been hampered by the biological complexity of stem cells and by limited federal research support. We propose to develop “embryonic stem cell-like” cells, that have been shown in animal models to have pluripotency properties similar to true embryonic stem cells, using adult testis tissue, and not human embryos, as the cell source. This research is based on the recognition that early germ cells (cells later destined to become sperm) in the testis are likely to be pluripotent, unlike other cells in the body. In other words, they have the power to either self-renew or to generate another cell type. As shown in mouse studies, it is possible to extract and culture the critically important testis stem cell (spermatogonial stem cells) in a Petri dish for prolonged periods of time. Under specific and precise culture conditions, it is also possible to “reprogram” these stem cells, or to uncover their pluripotency potential, so that they the gain the properties of true embryonic stem cells. Although these cells are not actually obtained from embryos, these “embryonic stem cell-like” cells perform many activities of true embryonic stem cells, including self-renewal or the ability to develop into other cell types in the body.
Work in our laboratory suggests that we also can obtain these early germ (spermatogonial) stem cells from adult men after a testis biopsy. Additionally, in specific culture conditions, we were able to coax these stem cells into cells that looked identical to embryonic stem cells. Despite early success, our first attempts to grow these cells for prolonged periods to verify their identity was not successful. We reasoned that we had not created the optimal culture conditions for these cells to “reprogram” or to uncover their pluripotency. Thus, one aim of this proposal is to study culture conditions, including systems that employ embryonic stem cells, to generate an optimal environment for reprogramming testis stem cells into embryonic stem cell-like cells.
Since one goal stem cell therapy is to repair damaged tissues in diverse diseases and individuals, another aim of this study addresses this issue. Because diseases are not limited by age or ethnicity, we will derive embryonic stem cell-like cells from individuals of various ages and ethnicities. We will determine whether the age or ethnicity of the stem cell donor affects our ability to generate embryonic stem cell-like cells. Perhaps it is more difficult to generate stem cells from men who are older compared to younger, or men of certain ethnicities compared to others. This information will have important clinical implications if testis based stem cell therapy is used to treat disease in the future. In summary, through this research we hope to obtain pluripotent stem cells that could potentially be used to treat disease in half the world’s population, without using embryos.
Statement of Benefit to California:
Five decades ago, a fledgling electronics and computer chip industry began to flourish in California. Known now as Silicon Valley, it was the vanguard of one of the world’s greatest industrial revolutions. Three decades ago, biotechnology also found a stronghold in California, and since then has blossomed into an industry of similarly profound size and productivity. Research in stem cell biology, enabled by Proposition 71, is yet another example of a burgeoning revolution that will maintain California’s competitiveness and reputation as the nation’s premier state for biomedical research. As Florence served as a magnet for education and the arts during the Renaissance, California, with its long history of entrepreneurial energy and new interest in funding stem cell research, now has the ability to draw into its fold the best minds in biomedical science with the potential for research funding in one of the most promising fields that biomedical research has ever witnessed.
The research, which will use known hESC lines to help create and characterize patient-specific, embryo-free, pluripotent stem cells of potential benefit to half of the world’s population, is uniquely suited for CIRM funding and will benefit the California on several fronts. Through its broad scientific approach and requirement for a highly skilled, broadly trained and multidisciplinary team, this proposal assembles a cohesive group of talented clinicians and scientists, including the hiring of others (post-doctoral fellow), who will work together to improve our ability to recruit and retain premier scientific minds in California. In addition, the mentoring abilities of the lead scientist and the project collaborator are robust, further contributing to the training of future stem cell scientists in California. Lastly, multidisciplinary interactions are essential not only for solving today’s problems in stem cell biology, but they also form a crucible for gestating the next generation of ideas and discoveries. In this way, California’s reputation at the premier state for stem cell research will be maintained, even as other states including Massachusetts, New Jersey, Connecticut, Maryland and Illinois consider similar state-supported, stem cell propositions.
In addition to the importance of a broadly trained team to the discovery “process” in the proposed research, the “content” of this proposal will add value to California in the form industry collaborations and patents. Given that a vibrant biotechnology industry coexists with academic centers in California, one can foresee this research in non-embryo-based, pluripotent stem cell technology being carried to its full clinical potential as cell-based therapy through academic-industry collaboration. Finally, by funding this proposal with limited federal funding opportunities, California will maintain its competitiveness as a global leader in high quality, clinically driven, embryonic and non-embryonic stem cell research.