A critical open question in regenerative medicine is how to create successful stem cell therapies that yield regenerative growth healing the patient but without giving them cancers which are thought to be the most likely side effect of these types of therapies. One step toward achieving this goal of having human embryonic stem cells (hESC) that are as effective and safe as possible is to identify (1) the stem cell factors that promote the properties of stem cells to regrow organs and (2) the factors that promote cancer formation. With this information we can "customize" hESC to be more functional but not cause cancer. Unfortunately because cancer is a highly related process to regenerative organ growth, the prediction is that the same factors that would tend to enhance the ability of stem cells to mediate regenerative growth are also likely to promote cancer. One example of such factors is the myc family of proto-oncogenes. The main objective of this proposal is to test the hypothesis that the concentration of Myc in hESC determines their regenerative and cancer capacities. We predict that we can identify an optimum amount of Myc that will yield hESC that have enhanced regenerative medicine properties without increased risk of cancer. To this end, we will conduct studies where we selectively raise or lower the amount of Myc in hESC and follow the properties of the "low Myc" hESC, "medium Myc" hESC, and "high Myc" hESC using in vitro assays as well as in vivo assays in mice for regenerative growth in injury models and for tumorigenesis. Our broader goal is to test the novel and risky hypothesis, that we can harness an oncogene to work in a beneficial manner in hESC to promote better regenerative medicine.
There is great promise in the potential use of human embryonic stem cells (hESC) for regenerative medicine therapies to treat a number of serious medical disorders such as liver disease, blood disorders, neurological disorders, diabetes, heart disease and other conditions. An important place to begin building a foundation for such therapies is to increase our understanding of how hESC function, specifically what makes them more likely to mediate regenerative organ growth and what makes them more likely to cause the unacceptable side effect of cancer. The proposed research, investigating the master regulators of hESC normal and cancerous function, will be of great benefit to the State of California. These studies will promote our ability to use hESC in a safe and effective manner and may allow us to customize hESC lines with an optimum amount of Myc that promotes their beneficial activity while eliminating the risk of cancer.