To make “mini muscles” from stem cells, you need the protein BAF60C.
Pier Lorenzo Puri, Ph.D., and his team study what makes a muscle cell just that—a muscle cell. They’re especially interested in applying that information to regenerate new muscle for people with muscular dystrophy.
Last year, the team discovered that two proteins called MyoD and BAF60C work together to mark the DNA of precursor cells, setting them on a course to become muscle cells. When the MyoD/BAF60c complex receives the right signals, it unwinds the cell’s genome and begins the process of producing muscle-specific proteins. This chain of events eventually triggers these precursor cells—those that hang out in our normal muscle tissue—to mature into new muscle cells.
This precursor cell-to-muscle cell conversion process slowly becomes exhausted in muscular dystrophy patients. Their resident precursor pool can’t keep up with the demand for new muscle as the person exercises and ages, eventually leading to weakness and immobility.
Stem cells to muscle cells
Over the past decade, researchers around the world have been using pluripotent stem cells—embryonic or induced in the lab—to generate unlimited quantities of other cell types. Pluripotent stem cells are useful because they have the ability to do two unique things: 1) self-renew, producing more stem cells and 2) differentiate, becoming any specialized cell type, like neurons or heart cells.
Harnessing these stem cell properties has been a boon to studies of health conditions like Alzheimer’s and heart disease. But muscular diseases like muscular dystrophy have lagged, in part because embryonic stem cells sitting in a laboratory dish don’t readily become skeletal muscle cells.
In a study published March 7 in Cell Reports, Puri’s team discovered that BAF60C is repressed in pluripotent stem cells. This lack of BAF60C is what keeps stem cells from readily differentiating into skeletal muscle cells. In fact, the mere presence of BAF60C marks a stem cell’s transition from pluripotency to differentiation.
Mini muscles for muscular dystrophy drug development
Puri’s team also developed a method for introducing BAF60C into embryonic stem cells. From there, MyoD/BAF60C primes the genetic landscape for muscle formation. Not only do muscle cells emerge from this new technique, but Puri’s team can also manipulate them into forming small, three-dimensional spheres that contract just like regular muscles. These “mini muscles” will be valuable laboratory tools for studying muscle development and conditions in which muscle malfunctions, like in muscular dystrophy.
“Now that we know how to make muscle from embryonic stem cells, we’re moving on to do the same using induced pluripotent stem cells derived from patients with muscular dystrophy,” Puri said. “This will allow us to study how the disease develops and test potential new therapies—in a way that’s personalized to the individual patient.”
This study was funded by the U.S. National Institutes of Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases grants R01AR056712, R01AR052779, and P30AR061303) and the Muscular Dystrophy Association.
Albini S, Coutinho P, Malecova B, Giordani L, Savchenko A, Forcales SV, & Puri PL (2013). Epigenetic Reprogramming of Human Embryonic Stem Cells into Skeletal Muscle Cells and Generation of Contractile Myospheres. Cell reports PMID: 23478022