image of boris hinz and microscopes

Bio-mechanical “memory manipulation” programs stem cell therapies for success

For the first time, scientists at the University of Toronto have identified micro RNA-21 as a key driver of “environmental” memory in stem cells ­­– but it’s how scientists may be able to manipulate those memories that could lead to a major breakthrough in stem cell medical interventions.

The study, published in Nature Materials, looked at how the micro RNA “imprints” local mechanical memory in mesenchymal stem cells (MSC’s)–cells which can be used in cell therapies to support the repair of severely damaged tissues.

We’re preloading these stem cells for success.

Cell cultivation is a particularly tricky step in these cutting-edge therapies: once stem cells are harvested from a host, the cells need to be grown to sufficient numbers for any transplantation to be effective. A single burn wound or a damaged heart, for instance, require billions of MSCs to support healing.

But during this proliferation process, these cells are stimulated by the mechanical environment, often acquiring scarring features that are retained post-transplantation, which can later result in organ failure and death. In fact, the scarring that derives from this phase of stem cell cultivation may be a major cause of stem cell transplantation failure.

“In clinical trials, for people injected with MSCs, it’s kind of a 50/50 positive or negative outcome,” said Hinz, lead author of the study and Distinguished Professor in the Faculty of Dentistry and the Institute of Biomaterials and Biomedical Engineering (IBBME) at the University of Toronto.

How can this success rate be improved? The researchers think this could very well be accomplished by manipulating the cells’ memories.

The team coined the term “mechanical memory” to explain how cells “imprint” their environments, which then permanently affect their functioning. Traditionally, these cell populations are grown on polystyrene plastic petri dishes which ultimately turn them into scar-promoting cells. After several weeks on a scar-stiff material, the cells’ miR-21 works to ‘imprint’ the stiffness of this environment. When later grafted into a host, the group proposed that these same cells can carry this fibrotic memory into the tissue.

Conversely, MSC’s grown on soft surfaces – surfaces that mimic the softness of organs like skin – retained their therapeutic potential after being delivered to a wound. What’s more, the mechanical memory of the growing environment was observed to last for weeks. 

“We’re preloading these stem cells for success,” said Hinz.

“The most exciting part of this research is the identification of miR-21 as the memory keeper,” said Chen Li (MSc IBBME 1T4), first author of the study who is currently undertaking a law degree at the University of Toronto, who nevertheless cautions that more needs to be determined as to the role of miR-21 and other potential “memory keepers.”

Still, the “platform technology” of “stiffness-tuned” surfaces for growing MSCs could soon lead to a revolution in stem cell therapies. “The advantage here is using surface mechanics as the regulatory factor,” added Hinz, as the study points to strategies that require no chemicals or genetic alterations at a cellular level – alterations which could be harmful to the host down the road. Instead, by relying on training the cells’ mechanical memory, the cells themselves remain in a pristine state, and function better.

“These findings would be an important landmark in boosting cell therapies, making them safer and hopefully more effective,” said Nilesh Talele (PhD 1T5), co-first author of the study and a current research fellow at Massachusetts General Hospital’s Cancer Center and Harvard Medical School.

The team is currently investigating what happens to these “pre-educated” cells post-transplantation

“We don’t know what these cells are actually doing in the wound environment,” explained Hinz. “We think they are educating other cells around them, telling other cells what to do – the cells act on other cell populations.”


Image: courtesy Jeff Comber, IITS