Fungus Toxin Triggers Stem Cells to Become Bone

Imagine you’re riding your bike and an unseen tree root sends you flying over the handlebars. You stick an arm out to break your fall, except the force is too much. The bones in your forearm snap like a twig.

A trip to the hospital means you’ll either get a cast or surgery to realign the broken bones so that they can heal properly. Afterwards, it can take up to six months before the bones fully recover. Now, though, University of North Carolina School of Medicine doctors say there might be something on the horizon to significantly decrease the time it takes for bones to reform after injury.

In an unexpected find, they watched a toxin called cytochalasin D (CytoD), which is produced by certain molds, cause stem cells to transform into new bone cells. The process can be seen in the gif above, with a stem cell exposed to CytoD beginning the process of turning into a bone cell. After seeing this change occur in cultured cells, Dr. Janet Rubin and colleagues injected it into mouse shinbones, where they witnessed “abundant bone formation” after just one week.

The team introduced CytoD to mesenchymal stem cells, which have the ability to develop into either fat or bone. The molecule broke up filaments of actin, a protein that is an essential part of the cytoskeletal fiber network, which span across the cell. These actin pieces then migrated into the stem cell’s nucleus within 30 minutes and altered the cell’s gene expression, essentially forcing it to become a bone cell. Their work was published recently in the journal Stem Cells.

“This was not what we expected,” said Rubin. “This was not what we were trying to do in the lab. But what we’ve found could become an amazing way to jump-start local bone formation.“



She said she did not believe CytoD’s effect on mesenchymal stem cells when a researcher in her lab, Dr. Buer Sen, showed her the initial results. “My first reaction was, ‘No way, Buer,’” Rubin said. “‘This must be wrong. It goes against everything in the literature.’ But he said, ‘I’ve rerun the experiments. This is what happens.’”

The group then tried CytoD in live mice, injecting it into their tibias. After letting it work for a week, they harvested the bones and looked for new bone growth. And while the mycotoxin might not end up being the therapy that could one day improve bone healing, the important part of their finding was uncovering the mechanism makes stem cells become bone.

“The data and images are so clear; you don’t have to be a bone biologist to see what cytochalasin D does in one week in a mouse,” she said. “Amazingly, we found that the actin forms an architecture inside the nucleus and turns on the bone-making genetic program.”



Top Gif: To monitor the actin transport into the nucleus of live cells, RFP-labeled actin was transfected into human mesenchymal stem cells: after CytoD treatment, stress fibers disassembled quickly and accumulated in the nucleus within 30 minutes (Right). Gif created from video. Video and caption courtesy of Sen et al./Stem Cells.