A Novel Microenvironment-Mediated Functional Skeletal Muscle from Human Embryonic Stem Cells and their In Vivo Engraftment
New Faculty II
$2 300 569
Statement of Benefit to California:
Muscular dystrophy (MD) comprises a group of skeletal muscle diseases that includes Duchenne muscular dystrophy (DMD) the most common and severe form of the disease, which afflicts 1 in 3,500 males. There are currently no means of treating this disease. Whereas transplantation of myogenic adult stem and progenitor cells may ameliorate the symptoms of MD (in animal models), such potential clinical treatments are limited by the scarcity of such cells. The applicant proposes to direct the differentiation of human embryonic stem cells into myogenic progenitor and more differentiated muscle cells. The applicant proposes to accomplish differentiation along the muscle lineage by first defining the optimal extracellular matrix and growth factor requirements for this process using a microarray platform. Thereafter physical cues will be used to further expand and differentiate the myogenic cell pool. Evidence that these procedures work to generate functional myoblasts will be obtained by assessing the capacity of the cells to ameliorate muscle wasting in a mouse model. The applicant proposes to investigate two federally approved and one non-approved human embryonic stem cell (hESC) line, along with induced pluripotent cells (iPS). Reviewers recognized the clinical significance of the proposed study. Reviewers were generally supportive of this ambitious research plan, which was described as exciting and easy to read. While two reviewers pointed out that successful execution of this proposal is contingent upon the investigator’s ability to produce the myogenic precursor cells (the focus of the first aim), the panel was uniformly supportive that the investigator had the skills, training and support to be successful in this endeavor. Reviewers commented on the novelty of the combinatorial platform with which the applicant proposes to achieve differentiation, and should allow the applicant to screen combinations of extracellular matrix concentrations and other factors quickly. This will be followed by attempts to grow the myogenic-differentiated hESCs in a physiologically-relevant three-dimensional microenvironment with which the applicant has had previous experience. While reviewers noted the innovation of this process, one cautioned that the mechanical stress stimuli could also drive unwanted terminal differentiation patterns which could render the cells unsuitable for subsequent transplantation. Reviewers judged this to be an excellent candidate for this RFA. They noted a number of high quality publications in the area of proposed research. The applicant has identified excellent mentors, including expertise in stem cell biology which was felt to be critical in this proposal. The applicant’s career development plan was well thought out, with reviewers citing that the current dual-appointment position reflects the applicant’s background and career development goals. One reviewer commented that this is an ideal candidate for this award; the applicant is a chemical engineer now working in bioengineering. Reviewers felt that the institutional support was excellent, noting a strong letter from the PI’s chair. The institution has a strong stem cell biology program, and has committed appropriate resources to the project. One concern voiced by several reviewers was the requirement that the applicant teach a two-course load. If the applicant is the sole course instructor, reviewers felt that this could limit the applicant’s ability to successfully pursue the research proposed in the application. In summary, panelists found the application to be innovative and high risk, but felt that the applicant could achieve the stated goals. The PI was judged to be well-trained, and an ideal candidate for the New Faculty II Award. Institutional support was also viewed as a strength of the application, with the one caveat that a heavy teaching load could impede the proposed research.