Researchers from the Harvard-affiliated Brigham and Women’s Hospital (BWH) have successfully cultivated miniscule muscle fibers from embryonic stem cells, offering a better model for studying muscular diseases, such as muscular dystrophy.
Skeletal muscle is one of the most abundant tissues in the body and also the target of many highly debilitating diseases, such as muscular dystrophy, sarcopenia and cachexia. Previously, skeletal muscle has proven difficult for laboratories to produce in amounts sufficient for clinical trials, potentially hindering treatment synthesis.
During embryonic development, skeletal muscles arise from somites, which derive from the presomitic mesoderm (PSM). This study, published in Nature Biotechnology, reports that using the natural development of PSM as a guide, the team were able to identify and mimic the important developmental cues, establishing the correct conditions for the differentiation of mouse embryonic stem (ES) cells into PSM-like cells. From this point, the researchers were able to drive cells to grow into millimetre-long muscle fibers capable of contracting in a dish and multiplying in large numbers.
Senior author, Dr Olivier Pourquie of Harvard Medical School’s Department of Genetics and BWH’s Department of Pathology commented, “We took the hard route: We wanted to recapitulate all of the early stages of muscle cell development that happen in the body and re-create that in a dish in the lab. We analysed each stage of early development, and generated cell lines that glowed green when they reached each stage. Going step by step, we managed to mimic each stage of development and coax cells toward muscle cell fate.”
Pourquie and his team found that a combination of secreted factors, important during early embryonic development, are also essential for stimulating differentiation. With this is mind, the researchers were able to produce long, mature fibers in a dish, derived from mouse and human pluripotent stem cells. This was contrasted with stem cells cultured from dystrophin-deficient mice, a model of Duchenne muscular dystrophy (DMD), highlighting the abnormally branched pattern that DMD muscle fibers show in the body.
This study also found that mouse ES cells differentiated into immature satellite cells could produce muscle fibres when grafted into a DMD mouse model, offering early promise for future treatment options.
“This has been the missing piece: The ability to produce muscle cells in the lab could give us the ability to test out new treatments and tackle a spectrum of muscle diseases,” concluded Pourquie.
Further study is now needed to determine if this new strategy could be optimised to develop cell therapies for treating degenerative muscular diseases in humans.
Sources: Potential treatment for muscular dystrophy. Haley Bridger. http://news.harvard.edu/gazette/story/2015/08/potential-treatment-for-muscular-dystrophy/; Differentiation of pluripotent stem cells to muscle fiber to model Duchenne muscular dystrophy. Chal, Orginuma, Tanoury et al. Nature Biotechnology doi: doi:10.1038/nbt.3297
Image: Researchers have been able to grow differentiated muscle fibres (green) in the lab. The nuclei are shown in blue. Image courtesy of Olivier Pourquie