Engineers at the Georgia Institute of Technology have figured out a cell-based approach to healing damaged muscle that could offer a more efficient method than those currently used.
Engineers at the Georgia Institute of Technology have figured out a cell-based approach to healing damaged muscle that could offer a more efficient method than currently used. Rather than implanting tissue, the researchers focus on delivering the cellular ingredients to regenerate muscle.
When the body recovers from a muscular injury, it relies on a kind of stem cell called a muscle satellite cell. These cells accomplish what surgical intervention can’t: They differentiate to form new muscle fibers, and fuse with existing muscle to repair an injury.
Transplanting these muscle satellite cells could eventually offer patients a better shot at muscular healing. Older patients, and those with genetic muscular dystrophy conditions, stand to benefit most. Both aging and muscular dystrophy leave patients with fewer and less functional muscle satellite cells.
But delivering muscle satellite cells to an injury is more complicated than injecting a slurry of cells into tissue.
“If you just implant the muscle satellite cells into the muscle itself, the surrounding environment actually kills the young stem cells,” said Young Jang, a professor of biomedical engineering who is leading the effort.
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Muscle satellite cells rely on external signals — both chemical and mechanical — to operate. Without a surrounding structure that prompts the cells to differentiate, the cells stagnate. The immune system flags that as atypical behavior and demolishes the offending cells.
Jang’s solution is to suspend the regenerative muscle satellite cells in a hydrogel — a jello-like material that mimics the natural cellular environment in multiple ways.
The hydrogel’s structure provides mechanical stimuli that directs the muscle satellite cells to grow and multiply. Certain chemicals mixed in the hydrogel cues the cells to perform different functions, and helps them survive.
Housing stem cells in hydrogels is not a new idea in the field of regenerative medicine. Many researchers working with stem cells for muscle recovery have focused on hydrogels made of biological proteins like collagen, fibrin, and laminin.
Naturally derived hydrogels mimic many important aspects of human tissue. But tuning their properties and achieving consistent materials can be difficult. That presents a problem in terms of scale-up and systematic testing.
To control the muscle stem cells’ environment more precisely, Jang and his team chose to use a synthetic hydrogel. Four-armed molecules — polyethylene glycol-maleimide — link together to form the chains of the gel’s structure.
These building blocks also react nicely to hold a variety of other chemicals within the gel, making it highly tunable. “It's a versatile system that we can mix and match,” Jang said.
In recent experiments, Jang and his team aimed to create hydrogel conditions that coaxed muscle satellite cells to develop into muscle fibers and survive.
Including the right proteins in the hydrogel proved to be especially important. When hydrogels contained a specific set of adhesive proteins — peptide sequences targeting an adhesive protein called integrin — muscle satellite cells differentiated and fused together, forming muscle fibers that were able to contract.
Cells growing in hydrogels without those peptide sequences, on the other hand, couldn’t fuse together to form complete muscle fibers.
Jang and his team also designed these gels to degrade over time, leaving space for the muscle satellite cells to grow. Degradable hydrogels turned out to be important for cellular survival: Muscle satellite cells in degradable gels formed healthy colonies, while their counterparts in nondegradable gels did not.
Armed with a hydrogel formulation to support stem cell function, Jang and his colleagues tested the system to heal leg injuries in mice. They applied the hydrogel-encapsulated muscle satellite cells topically to exposed muscular injuries and found promising results.
The cells fused with existing muscle and formed new fibers in both aging mice and mice with muscular dystrophy.
For these experiments, Jang and his team isolated muscle satellite cells from young mice, but translating this kind of therapy into human medicine will require different avenues of cell sourcing.
Induced pluripotent stem cells — cells that can be coaxed to divide into a number of different cell types — may be one avenue for creating large volumes of muscle satellite cells. But that could be a ways down the road, and researchers will need to be careful with the risks inherent in encouraging cell division. “We don't want to make tumor just to cure a muscle,” Jang said.
With cell sourcing advancements, delivering muscle satellite cells via this kind of hydrogel vehicle could open up many options for regenerative medicine.
Because the hydrogel is a liquid with controllable gelation, clinicians might one day deliver hydrogel-encapsulated muscle satellite cells intravenously, sending regenerative cells wherever they’re needed throughout a patient’s body, Jang said.
Including different chemical cues at different phases of injury could improve muscular recovery over long periods of time — from healing to rehabilitation — thanks to the inherent versatility of a synthetic hydrogel system.
Menaka Wilhelm is an independent writer focusing on technology.
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