Stanford Medicine Scope - December 19, 2024 - by Nina Bai
Manish Ayushman, a PhD student in bioengineering, has watched more than a thousand hours of microscopic footage of stem cells in the lab. At first, the cells seemed like they weren't doing much of anything. But when Ayushman looked a little more closely, he noticed they were moving ever so slightly - turning and pulsing to a languid tempo.
When he sped up the footage, the movements became clearer: Each stem cell appeared to be shimmying and shaking with purpose.
In a paper published Nov. 1 in Nature Materials, Ayushman and Stanford Medicine colleagues described this previously unknown type of cell movement, which they've named cell tumbling. Unlike known types of cell movement, such as spreading and migration, which take hours to days, cell tumbling is relatively quick, taking seconds to minutes.
"We're still exploring how the cells actually tumble and why they do it, because they are spending a lot of their energy doing it," Ayushman said.
Sped up video comparing stem cells tumbling in sliding hydrogel (left) and stem cells prevented from tumbling in conventional gel (right).
The study suggests that tumbling helps stem cells do what they are famous for - transform into different cell types.
It also suggests that differentiation depends not only on chemical signals - which is how researchers typically induce stem cells to differentiate in the lab - but also physical signals.
"We're discovering how cell tumbling alters the way cells sense and respond to physical forces from their microenvironment and how that changes their differentiation outcomes," said Fan Yang, PhD, associate professor of orthopaedic surgery and bioengineering, who is the senior author of the study.
Yang's lab is dedicated to developing biomaterials-based therapies that regenerate human tissues lost to disease or aging. In the new study, her team focused on transforming stem cells into cartilage.
"Cartilage is one of the most commonly injured tissues in the human body, yet has very limited capacity to regenerate," Yang said.
To study cells in a 3D environment approximating what they experience in the body, researchers embed them in small tubes of water-based gelatin. But the rigid gels conventionally used for this purpose restrain cell movements. Yang's lab developed a new type of gel, called sliding hydrogel, which is malleable enough to allow smaller, localized cell movements.
In an earlier study, they were surprised to find that stem cells embedded in the new sliding gel differentiated into cartilage much faster than those in conventional gels.
"It's a very striking difference," Ayushman said. "That triggered our curiosity, and we decided to dig deeper."
A thousand hours of cell footage and many experiments later, the researchers believe the difference comes down to cell tumbling.
They found that tumbling occurs mainly in the first four days of differentiation, a process that can take weeks to complete. After the researchers chemically induced stem cells to differentiate into cartilage, those allowed to tumble unimpeded in that critical period eventually formed the most cartilage. Any disruption to tumbling in the first four days resulted in less cartilage.
The team also found that although the entire cell tumbles, the nucleus within the cell experiences the greatest motion, like laundry being tossed around in a dryer. That led the researchers to wonder if tumbling could affect how the DNA inside the nucleus is transcribed.
Inside the nucleus, long strands of DNA are packaged in bundles known as chromatin, which can be loosely wound, to make more DNA accessible to transcription, or tightly wound, to limit transcription.
"Stem cells are known to have a more open chromatin state because they are supposed to be able to differentiate into multiple lineages," Ayushman said. "But to commit to a specific lineage, they need to condense their chromatin - and cell tumbling seems to help with that."
The jostling of the nucleus may adjust the chromatin into tighter bundles, committing a stem cell to a particular fate. Indeed, using a special type of gene sequencing, the researchers confirmed that tumbled stem cells had more closed chromatin overall, but more access to select regions needed for differentiation.
They showed that cell tumbling enhances stem cell differentiation into other tissues in the lab, such as bone and fat, though they do not yet know whether it occurs naturally in the human body. Ultimately, the researchers hope to translate the new discovery into more efficient ways to generate replacement cartilage and other tissues from a patient's own stem cells.
Though the team eventually settled on the term "cell tumbling," the movements may be more carefully choreographed than the name suggests. Stem cells induced toward different lineages move in distinctive ways. To Yang, would-be cartilage cells seem to waltz around and around, while would-be bone cells swing back and forth, and would-be fat cells vibrate in place, like tap dancing.
