Treating mice with a compound that increases the expression of the inactive protein helped them heal from injury along with less scarring, according to a study by researchers at the Stanford University School of Medicine.
The researchers are hopeful that their findings can one day be used to help keep muscles supple during normal ageing and to treat people with diseases like muscular dystrophy.
“Fibrosis occurs in many degenerative diseases and also within normal aging, ” said Thomas Rando, MD, PhD, a professor of neurology and neurological sciences. “It negatively impacts muscle regeneration by altering the come cell niche and inhibiting the stem cell perform. In addition , as more scarring occurs, muscles become stiff plus can’t contract and relax smoothly. ”
Rando, who is the director of Stanford’s Glenn Middle for the Biology of Aging, is the senior author from the study, which will be published online Nov. 28 in Nature . Former graduate student Alisa Mueller, MD, PhD, is the lead author.
Self-policing stem cells
The experts discovered that stem cells embedded in muscle fibers do a couple of fancy gene-expression footwork in order to respond appropriately to injuries, disease or aging. In particular, the cells toggle between creating a full-length, active version of a protein that responds in order to external signals to divide and a shorter, inactive edition of the same protein that attenuates the growth transmission and prevents an overly enthusiastic response that can result in scarring or fibrosis.
The researchers analyzed a protein called platelet-derived growth factor receptor alpha dog, or PDGFR alpha, that sits on the surface of muscle-embedded stem cells called fibro-adipogenic progenitors, or FAPs. These types of stem cells are responsible for generating the connective tissue scaffolding necessary to support muscle development and regeneration.
PDGFR alpha straddles the cell membrane. The part outside the cell serves as a landing pad for exterior signals that encourage the FAPs to begin dividing, or even proliferating. The interior portion of the protein passes the transmission along to other proteins inside the cell to get the ball moving. Although some proliferation is necessary to repair an injury, an overly passionate response can lead to scarring and fibrosis that inhibits muscle mass function. So it’s imperative the cells strike the right balance within their response.
The researchers found that the tissue have devised a novel, unexpected way to police on their own. The cells found a way to generate a shortened version from the protein that is missing the interior portion of its structure. This particular shortened version hangs out on the cells’ membranes plus sequesters the growth signals away from the active type of PDGFR. Without the interior part of the protein, the message to develop is stopped in its tracks.
“We’ve discovered that the cells actively regulate the production of the inhibitory type of the protein, which is very surprising, ” said Rando. “If they make less, the degree of fibrosis increases; when they make more, it decreases. ”
The pv cells produce the shortened form of the protein by spotting and using a specific series of nucleotides in the messenger RNA that will encodes the instructions to make the PDGFR alpha protein. The particular nucleotide code tells the cell’s messenger RNA-processing equipment to create a shorter-than-normal message. As a result, the protein that is made out of that messenger RNA is also truncated.
Artificially increasing, decreasing expression
Mueller, Rando and their colleagues used a type of small particle called a vivo-morpholino that can bind and block entry to small sections of messenger RNA to artificially increase or even decrease expression of the inhibitory version of the PDGFR leader protein. They found that increasing the amounts of the particular inhibitory version allowed both young and old mice to cure from injury with less fibrosis and scarring. On the other hand, decreasing the amount increased the severity of fibrosis.
“We’d like to test this approach in a mouse type of muscular dystrophy next, ” said Rando. “Interestingly, the particular vivo-morpholino we used is similar to a small oligonucleotide therapy getting tested in clinical trials to stimulate the production associated with proteins missing in patients with Duchenne muscular dystrophy. Perhaps we could also use this approach to reduce fibrosis with this disease. ”