Exploiting stem cells for their restorative properties is the primary underlying goal of regenerative medicine. Now, researchers at Johns Hopkins have identified a protein that plays a vital role in the lives of stem cells, which they believe can bolster the growth of damaged muscle tissue. The results from this new study could potentially contribute to treatments for muscle degeneration caused by old age and diseases such as muscular dystrophy.
The findings, published recently in Nature Medicine in an article entitled “Targeting β1-Integrin Signaling Enhances Regeneration in Aged and Dystrophic Muscle in Mice,” showed that the presence of the β1-integrin protein helped promote the transformation of undifferentiated stem cells into muscle after the tissue had degraded and improve regenerated muscle fiber growth as much as 50%.
While the presence of β1-integrin in adult stem cells is ostensible, the precise molecular mechanism it employs within these cells has not been examined, especially its influence on the biochemical signals promoting stem cell growth.
The Hopkins team found that that β1-integrin—one of 28 types of integrin—maintains a link between the stem cell and its environment and interacts biochemically with fibroblast growth factor (FGF) to promote stem cell proliferation and restoration after muscle tissue injury. Aged stem cells do not respond to FGF. The results also showed that β1-integrin restores aged stem cells' ability to respond to FGF to grow and improve muscle regeneration.
“We show that β1-integrin is an essential niche molecule that maintains SC [satellite cell] homeostasis, and sustains the expansion and self-renewal of this stem cell pool during regeneration,” the authors wrote. “We further show that β1-integrin cooperates with fibroblast growth factor 2 (Fgf2), a potent growth factor for SCs, to synergistically activate their common downstream effectors, the mitogen-activated protein (MAP) kinase Erk and protein kinase B (Akt).”
The investigators were also able to track an array of proteins inside the stem cells, testing the effects of removing β1-integrin. This is based on the understanding that the activities of stem cells are dependent on their environment and supported by the proteins found there.
"If we take out β1-integrin, all these other (proteins) are gone," stated senior study author Chen-Ming Fan, Ph.D., adjunct professor of biology at Johns Hopkins and staff member at the Carnegie Institution for Science in Washington, DC, and Baltimore. This result perplexed the researchers, but the experiment showed that without β1-integrin, stem cells could not sustain growth after muscle tissue injury.
After examining β1-integrin molecules and the array of proteins that they used to track stem cell activity in aged muscles, the authors found that all of these proteins looked like they had been removed from aged stem cells. The researchers subsequently injected an antibody to boost β1-integrin function into aged muscles to test whether this treatment would enhance muscle regeneration. Measurements of muscle fiber growth with and without increasing the function of β1-integrin showed that the protein led to as much as 50% more regeneration in cases of injury in aged mice.
Astonishingly, when the same β1-integrin function-boosting strategy was applied to mice with muscular dystrophy, the muscle was able to increase strength by about 35%. The Hopkins team was excited by their finding, but realize they have a long road ahead of them to work out the full biochemical mechanism
"We provide here a proof-of-principle study that may be broadly applicable to muscle diseases that involve SC niche dysfunction," the authors penned. "But further refinement is needed for this method to become a viable treatment."
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