Embryonic stem cells (ESC), originating from preimplantation embryos, are able to differentiate into any type of cells in our body. The generation of ESC lines deriving from human embryos (hESC) has attracted a lot of dispute among researchers, but raised the hope that one day hESCs can be use as a source of cells for cell replacement therapy in the treatment of degenerative diseases and cancer. Substantial efforts are currently focused on unveiling the full potential of hESCs by developing culture systems aimed at the selective differentiation in the cell type of interest. We set up specific culture conditions that allow hESC differentiation in the originator cells (mesenchymal precursors) that form the bones, cartilage and muscles in our body.
Muscular dystrophies (MD) are a group of diseases affecting the muscles in our body characterized by progressive muscle weakness and atrophy. There is no cure or treatment available for MD. In our preliminary studies, we further defined conditions for the specific generation of skeletal muscle cells from the hESC-derived mesenchymal precursors. We then converged our attention on their potential therapeutic applications. The specific aims of our proposed studies are: 1) optimization of this culture system to enhance skeletal muscle development during hESC differentiation. 2) Transplantation of these cells into animal models of MD (dystrophic mice and dystrophic dogs), to evaluate their in vivo functionality and their potential to repair or replace dystrophic muscle fibers.
Statement of Benefit to California:
The establishment of pluripotent stem cell lines derived from the human blastocyst (hESC) opened a new era in biomedical research. Because of their embryonic origin, hESCs can be virtually differentiated in all the cells of all tissues in our body. There is a great hope that one day hESC-derived specialized progeny will be used for cell-based therapy in the treatment of a variety of degenerative diseases and cancer. The California stem cell initiative with the institution of the CIRM will boost hESC research through the funding of innovative projects.
Muscular dystrophies (MD) are a group of > 20 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. There are many forms of muscular dystrophy, some noticeable at birth (congenital muscular dystrophy) and others in adolescence (Becker and Duchenne MD). Duchenne MD is perhaps the most common of them, with a worldwide incidence of 1 in 3,500 male births. Duchenne MD is the result of mutations in the gene that regulates dystrophin - a protein involved in maintaining the integrity of muscle fibers. Despite the substantial advances made in identifying the genetic defects causing these diseases, there is no treatment or cure available and affected children usually die in their teens. We propose to investigate the potential clinical applications of ESC-derived skeletal muscle cells upon transplantation in animal models of muscular dystrophy. We also investigate the molecular basis of skeletal muscle development during hESC differentiation.
This research proposal will benefit the State of California and its citizens in the following ways. First of all, Californians are not immune to any form of MD and the overall incidence of this group of diseases is the same as elsewhere, with devastating consequences for the affected individuals and their families. If our hypothesis proves to be correct and skeletal muscle cells derived from hESCs can efficiently repair dystrophic muscle fibers in animal models, the likelihood of the use of these cells for transplantations in MD patients is going to be high. Therefore, Californians will be the first to benefit from the outcome of the proposed research. In addition, successful ESC therapy of MD will certainly encourage and stimulate research for other ESC-based therapy for related diseases.
In conclusion, the CIRM initiative will undoubtedly lead to the discovery of a therapy and/or the developmental mechanisms leading to some disease and that in itself will put California at the top of ESC research with enormous benefits for all Californians.