Research & Discovery > Healing the Heart From Within

Healing the Heart From Within

Understanding how stem cell-secreted proteins spur regeneration is a move toward cell-free therapy.

By Jennifer Tsang, Ph.D. Illustration by Beth Goody

In a 2023 clinical trial, Mayo Clinic researchers found that stem cell therapy for heart failure improves quality of life in patients. But how stem cells work to heal the heart remained unknown.

“The holy grail of regenerative medicine is discovering the drivers of regeneration,” says Andre Terzic, M.D., Ph.D., Marriott Family Professor and Marriott Family Director, Comprehensive Cardiac Regenerative Medicine for the Mayo Clinic Center for Regenerative Biotherapeutics.

While one school of thought proposes that stem cells become new heart tissue, another possibility looks beyond the cells themselves. “Stem cells could help promote the heart’s own repair mechanisms,” says Armin Garmany, an M.D.-Ph.D. student at Mayo Clinic Alix School of Medicine. In other words, stem cells — through protein messengers — could instruct the body to repair itself after a heart attack. Dr. Terzic calls this "healing from within."

Scientists have seen hints of this phenomenon for years. “We observed that stem cells injected into the heart disappear,” says Dr. Terzic. “Yet, their benefit is long lasting.”

Dr. Terzic's team at Mayo Clinic wanted to understand how stem cells help repair damaged hearts without directly becoming heart tissue themselves. In 2024, supported by the Marriott Family Foundation, they published new research showing that proteins secreted by stem cells were linked to the heart’s recovery after heart attacks.

The power of secreted proteins from stem cells

The team began their study by programming stem cells for heart repair. When they delivered the stem cells to damaged hearts, they saw improvements in the hearts’ pumping function. These heart-repairing stem cells produced a wealth of proteins engaged in forming new heart tissue and blood vessels, in tissue regeneration, and in modulating the immune system. Using state-of-the-art technologies, the team identified nearly 2,000 stem cell-secreted proteins.

“We linked a subset of the secreted molecules to the repair signature of a stem cell-treated infarcted heart,” Armin says. In additional analysis, they found that functional improvements associated with stem cell therapy occur with increased levels of these secreted proteins. Conversely, when they simulated a deletion of critical proteins, the researchers found that the heart could no longer repair itself.

Forging a path toward cell-free treatment for heart failure

Stem cell therapies are challenging to produce at scale, requiring labor-intensive and cost-prohibitive procedures. Stem cells are also fragile and hard to transport.

This "interactome" image represents a map of the proteins secreted by the heart repair stem cells and how they interact with one another. This type of analysis helps scientists understand which proteins are the most important for heart regeneration by showing the relationships between key proteins.

By uncovering the secreted proteins that stem cells use to spur the heart's own healing processes, researchers are forging a path toward new cell-free therapies. This approach may even eliminate the need to transplant stem cells altogether.

Cell-free treatments offer manufacturing and delivery advantages. They’re more readily scaled, stored and administered to a patient, according to Dr. Terzic.

“Cell-free biotherapies can also be more accessible and affordable, potentially benefiting many patients,” adds Armin.

With over 80 million people worldwide suffering from heart failure, advancements like these give hope for a new class of future therapies for those facing this devastating condition.

“Understanding heart failure and how we can address it today with modern therapies has been most remarkable,” says Dr. Terzic. “Uncovering how the heart can be guided to heal itself opens up a new horizon in regenerative medicine.”