Late in May, the Brampton Fire Department (just outside of Toronto) held a “boot drive” to raise money for Muscular Dystrophy. My boyfriend who happens to be a firefighter tells me that boot drives are fairly common among Canadian fire departments. In fact, they are often specifically supporting Muscular Dystrophy Canada. At a boot drive, firefighters set up shop in community spaces and literally fill their boots with donations.
The fire departments have chosen a worthy cause to support as approximately 50,000 Canadians suffer from the disease. Muscular dystrophies are a group of neuromuscular disorders caused by genetic mutations resulting in progressive muscle weakness and muscle wasting. Severity of symptoms, age of symptom onset, speed of progression and muscles affected can very between each form of muscular dystrophy. These disorders may become severely debilitating or fatal over time as patients can lose the ability to walk, speak or even breath. Currently, there is no cure for muscular dystrophy.
Recently, an exciting report was published in Cell Stem Cell describing the generation of expandable muscle stem cells from human pluripotent stem cells. These muscle stem cells were transplanted into a mouse model of muscular dystrophy, engrafting into leg muscle and significantly improving muscle function.
While muscle stem cell (known as satellite cells) replacement strategies in muscle wasting conditions have long been a desired treatment strategy, we have not had access to a sufficient number of muscle satellite cells for transplantation. Enough satellite cells for transplantation cannot be obtained from a donor muscle without causing severe or permanent damage. In early clinical trials, small numbers of satellite cells were obtained, expanded ex vivo and then transplanted into Duchenne’s muscular dystrophy patients (the most common form of muscular dystrophy). However, no improvement was observed. It is thought that ex vivo expansion changes functional properties of the satellite cells.
The current study provides a novel, renewable source of muscle satellite cells that could one day be used for transplantation into human patients. To generate satellite cells, human pluripotent stem cells were first differentiated into mesoderm (the germ layer in which satellite cells are derived) and then the PAX7 gene was over-expressed. The result: an expandable pool of satellite cells that are capable of differentiating into mature, multinucleated myotubes.
When these satellite cells were transplanted into muscular dystrophy mice, high levels of engraftment were observed and engrafted cells could be detected 11 months following transplantation. Many transplanted cells had differentiated into mature myotubes but some did remain as satellite cells. This is important because the replacement of satellite cells means that new myotubes can be formed over time.
How does PAX7 expression create expandable satellite cells? The answer to this question can be answered, in part, by work from Michael Rudnicki and his group, who have been investigating how PAX7 works at the molecular level. Their work recently published in Developmental Cell describes the ability of PAX7 to bind directly do DNA regulatory regions (regions controlling gene expression) of genes involved in proliferation (cell expansion) and inhibition of muscle differentiation (important for maintaining satellite cell self-renewal). Rudnicki’s work provides important insight into the function of PAX7, which is distinct from other genes involved in muscle maintenance.
PAX7-induced human satellite cells as a renewable cell source is exciting but far from the clinic. But this work provides researchers a solid basis for optimization of a viable source of muscle satellite cells that could one day be used for cell transplantation therapies.
Angela C. H. McDonald
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