Induced pluripotent stem cells (iPSCs) hold much promise in regenerative medicine because they are derived from adult tissues and could be developed into other cell types in the body for potential transplants. But turning these new cells into functioning tissue has proven challenging. A research team at Duke University has managed to overcome significant hurdles to create the first functioning human muscle from iPSCs.
The development, described in Nature Communications, was based on work first published in 2015. “It's taken years of trial and error, making educated guesses and taking baby steps to finally produce functioning human muscle from pluripotent stem cells,” said Lingjun Rao, who co-authored the new study, in a statement.
Rao is a member of biomedical engineering professor Nenad Bursac’s lab, which had previously grown functioning muscle fibers from immature human muscle cells called myoblasts—cells that have already passed the stem-cell stage. The real-world problem with that approach is obvious: It would require taking muscle tissue from a patient already in desperate need of it, such as someone with Duchenne muscular dystrophy.
This time around, instead of using myoblasts, the researchers started with iPSCs. “[W]ith this technique, we can just take a small sample of nonmuscle tissue, like skin or blood, revert the obtained cells to a pluripotent state, and eventually grow an endless amount of functioning muscle fibers to test,” said Bursac.
Previous studies showed it was possible to transform iPSCs into cells that are similar to mature muscle cells but not quite as robust. Bursac’s study went one step forward by immersing iPSCs in a molecule called Pax7, which directed the cells to become muscle. And once the cells were about to complete the transformation, Bursac and Rao stopped the Pax7 supply and started nourishment and support so that they could fully mature.
“What made the difference are our unique cell culture conditions and 3D matrix, which allowed cells to grow and develop much faster and longer than the 2D culture approaches that are more typically used,” said Rao.
The resulting muscle reacted to stimuli such as an electric shock and biochemical signals mimicking neuronal inputs, just like natural muscle tissue, the researchers reported. When implanted into adult mice, the fibers survived and functioned for at least three weeks while integrating into native tissue. (For more, see the video below.)
Although the muscle isn’t equally strong as native muscle, the team is optimistic. The iPSC-derived method yielded many more “satellite-like cells” that are necessary for normal muscles to repair damage. It also allowed the researchers to grow more cells from a smaller starting amount.
The advancement could lead to new regenerative therapies and research models for rare diseases and precision medicine. In the future, the scientists hope to combine the technique with genetic therapies to fix genetic malfunctions at the iPSC stage and hence grow completely healthy muscle.