Basic Biology IV
The field of stem cell biology as it applies to regenerative medicine requires a detailed understanding of what controls stem cell function. Our primary interest, therapeutically, is to transplant highly potent muscle stem cells (MuSCs) into the muscles of patients with muscular dystrophies. This offers a hope for a potential treatment or even cure of these devastating disorders. One of the main challenges is that MuSCs exist almost exclusively in a dormant state called the “quiescent” state, and it is in this state that they hold the greatest potential to regenerate muscle. This poses a major hurdle for therapy since these cells are rare in the body. Thus, it would be ideal if they could be grown to large numbers in culture without losing any of the potency of the quiescent state. Our main goal is to understand what controls the quiescent state in a MuSC’s native environment, or its “niche”. To do this will be purify quiescent MuSCs from human muscle tissue and we study their molecular and functional properties, particularly those that regulate quiescence. In addition, we will create artificial MuSC niches in order to recapitulate, in culture, the key elements that maintain MuSC quiescence and regenerative potential in vivo. Ultimately, understanding the regulation of quiescence will be a major breakthrough in our goal to use MuSCs to treat muscular dystrophies.
Statement of Benefit to California:
A major benefit to California of our studies will be to bring hope to the tens of thousands of patients with muscular dystrophies living in the state and for whom there are minimal treatments and no cures for these diseases. Still, due to the growing field of regenerative medicine from the investment of the citizens of California in CIRM, this state has become the world leader in the development of stem cell therapeutics. Our research would contribute substantially to this enterprise. This is particularly important because, as of now, there is only a single clinical trial ongoing in the world to use stem cells to treat muscular dystrophies, and that is a very small trial (6 patients) based in Italy. Despite decades of research by hundreds of laboratories around the world, several hurdles remain to realize the therapeutic benefit that has been envisioned, and among those major hurdles are finding cells that are numerous and potent enough to be feasible vehicles for stem cell therapies. We and many others believe that muscle stem cells (MuSCs) are just those cells, but we have to discover how best to capitalize on the potential of these cells so that, upon transplantation, they can both regenerate entire muscles and replenish the endogenous MuSC population, something that has eluded researchers. This is the main goal of our research, and the successful completion would put California at the forefront of stem cell therapeutics for muscular dystrophies.
The overall goal of this application is to understand how skeletal muscle stem cells (MuSCs) maintain quiescence, a state in which cells are not dividing but are capable of re-entering the cell cycle. Since quiescent MuSCs possess the greatest potential to regenerate muscle, the applicant intends to purify such cells from human muscle tissue and investigate the molecular mechanisms that regulate this state. Given that the native environment, or niche, is known to contribute to the control of stem cell behavior, the applicant will then create artificial, bioengineered MuSC niches in vitro to examine the components that maintain MuSC quiescence and regenerative potential in vivo. Significance and Innovation - This application addresses a significant issue in skeletal muscle stem cell biology, and the applicantís rationale that understanding MuSC quiescence will be critical for advancing therapeutic applications is overall sound. - The applicant acknowledges that to use MuSC in potential therapies, methods need to be developed to generate enough of these cells while maintaining their quiescence. The applicant, however, does not directly address this important issue experimentally. - The concept that a niche environment controls stem cell quiescence is not a novel idea, but the use of the artificial MuSC niche provides an innovative direction for the field. Feasibility and Experimental Design - The proposed experiments depend on the isolation of healthy, quiescent MuSCs. However, the isolation process itself is known to be sufficient to drive these cells out of quiescence. It was therefore a major concern that the preliminary data are not conclusive as to whether the isolated cells remain quiescent. - Convincing evidence, including discussion of relevant published data as it relates to maintenance of the quiescent state after MuSC isolation, was considered insufficient. - Preliminary data are supportive of some of the proposed experiments, and demonstrate that the applicant has developed the technology for the bioengineered niche and accompanying assays needed for this project. - Reviewers questioned whether sufficient cell numbers could be obtained for some of the proposed experiments. Principal Investigator (PI) and Research Team - The PI, the research team and collaborators are outstanding and have the expertise to execute this study. - The PIís track record was a significant strength of the proposal. Responsiveness to the RFA - The application is fully responsive to the RFA.