Newts and many other amphibians can regrow limbs and heal wounds without scars, skills that researchers hope to bring to people.
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Lop the tail or a foot off a salamander and it will grow right back. Mammals aren’t so lucky--at least not yet. With the goal of developing a salve that heals wounds without scarring, researchers have now used small molecules to turn immature muscle fibers into cells that can morph into bone, fat, nerve, or muscle (ACS Chem. Bio., DOI:10.1021/cb200532v).
“In humans, if you damage the skin tissue, a scar will form,” says Darren Williams of Gwangju Institute of Science and Technology, in South Korea. Scar tissue is a mammalian all-purpose stopgap: It closes wounds but without the functionality of the lost or damaged tissue. Salamanders, however, don’t scar; rather, studies in amphibians have shown that the cells in their wounded tissue dedifferentiate to become stem cells, which in turn redifferentiate into the appropriate cell types for perfect healing.
Williams found last year that mammalian muscle cells could be coaxed into amphibian-like dedifferentiation if he added small interfering RNA that reduced cellular levels of p21, a protein that arrests cell growth and division (ACS Chem. Bio., DOI: 10.1021/cb2000154). But the siRNA was difficult to work with and caused some cells to die, so Williams scanned published reports for other small molecules to take down p21.The search led Williams to four molecules that he thought might trigger cells to dedifferentiate: lysophosphatidic acid, SQ22536 (an inhibitor of adenylyl cyclase), SB203580a (an inhibitor of p38 mitogen-activated protein kinase), and BIO (an inhibitor of glycogen synthase-3 kinase).
To test the four candidates, Williams and his team cultured mouse myotubes, the precursors to muscle fibers. Muscle fibers pose a particular challenge to any dedifferentiating compound because each cell contains multiple nuclei. Only single-nucleus cells can revert to stem cells. So the researchers first exposed the myotubes to myoseverin, a chemical that breaks multinucleated cells into single-nucleus cells. They then incubated the cells with each of the four candidate molecules for two days, after which they found chemical markers indicating that all four of the molecules had induced the cells to dedifferentiate and begin to divide. To establish that, like stem cells, the dedifferentiated cells could give rise to other types of cells, the researchers mixed them with chemicals that successfully converted the cells into fat, bone, muscle, and nerve cells.
Jeremy Brockes of University College London calls the work a “milestone” because myoseverin was discovered a decade ago, but Williams was the first to combine it with molecules that could make cells dedifferentiate. Brockes still questions whether myoseverin will work on full muscle fibers, as opposed to myotubes. Muscle fibers, he says, “seem significantly more challenging” because of their complex structure. Williams plans to address this in his next experiment: testing the healing powers of myoseverin and the p21 blockers on mice with amputated toes.
