How do you mend a broken heart? It’s a subject that songwriters have pondered for generations, without success. But if you pose the same question to a heart doctor, they would give you a number of practical options that focus on the prevention or management of the physical symptoms you are dealing with.

That’s because heart disease is complicated. There are many different types of diseases that affect the health and function of the heart. And once damage happens to your heart, say from a heart attack, it’s really hard to fix.

New regenerative factor for heart disease

Scientists from Stanford University, the University of California, San Diego, and the Sanford-Burnham-Prebys Medical Discovery Institute have teamed up to figure out how to fix a broken heart. In a CIRM-funded study published today in the journal Nature, the group reported that the gene follistatin-like 1 (FSTl1) has the ability to regenerate heart tissue when it’s delivered within a patch to the injured heart.

The wall of the heart is made up of three different layers: the endocardium (inner), myocardium (middle), and epicardium (outer). The epicardium not only protects the inner two layers of the heart, but also supports the growth of the fetal heart.

The group decided to study epicardial cells to determine whether these cells produced specific factors that protect or even regenerate adult heart tissue. They took epicardial cells from rodents and cultured them with heart cells (called cardiomyocytes), and found that the heart cells divided and reproduced much more quickly when cultured with the epicardial cells. This suggested that the epicardial cells might secrete factors that promote the expansion of the heart cells.

Patching up a broken heart

They next asked whether factors secreted from epicardial cells could improve heart function in mice after heart injury. They designed and engineered tiny patches that contained a cocktail of special epicardial factors and sewed them onto the heart tissue of mice that had just experienced the equivalent of a human heart attack. When they monitored these mice two weeks later, they saw an improvement in heart function in mice with the patch compared to mice without.

When they analyzed the cocktail of epicardial factors in the patch, they identified one factor that had potential for regenerating heart tissue. It was FSTL1. To test its regenerative abilities, they cultured rodent heart cells in a dish and treated them with FSTL1 protein. This treatment caused the heart cells to divide like crazy, thus proving that FSTL1 had regenerative qualities.

Moving from the dish into animal models, the scientists explored which layers of the heart FSTL1 was expressed in after heart injury. In healthy hearts, FSTL1 is expressed in the epicardium. However, in injured hearts, they found that FSTL1 expression was missing in the epicardium and was instead present in the middle layer of the heart, the myocardium.

FSTL1 to the rescue

In a eureka moment, the scientists decided to add a FSTL1 protein back to the epicardial layer of the heart, post heart injury, using the same patch system they used earlier in mice, to see whether this would promote heart tissue regeneration. Their guess was correct. FSTL1 delivery through the engineered epicardium patch system resulted in a number of beneficial effects to the heart including better function and survival, reduced scar tissue build up (a consequence of heart injury), and increased blood flow to the area of the patch.

Upon further inspection, they found that the FSTL1 epicardial patch caused heart cells to divide and proliferate. The same effect did not happen when FSTL1 is expressed in the myocardium layer of the injured heart.

To make sure their findings translated to other animal models, they studied the regenerative effects of FSTL1 in a pig model of heart injury. They applied patches infused with FSTL1 to the injured heart and as expected, observed that FSTL1 delivery improved symptoms and caused heart cells to divide.

No more heartbreak?

The authors concluded that heart injury turns off the activity of an important factor, FSTL1, in specific heart cells needed for heart regeneration. By turning on FSTL1 back on in the epicardium after injury, heart cells will receive the signal to divide and regenerate heart tissue.

Co-first author and CIRM postdoctoral scholar Ke Wei spoke to CIRM about the next steps for this study and its relevance:

Co-first author, Ke Wei

In the future, we hope that our engineered epicardium patch technology can be used as a clinical platform to deliver drugs or cells to the injured heart. This strategy differs from conventional tools to treat heart attack, and may provide a novel approach in our repertoire battling heart diseases.

Thus it seems that scientists have found a potential way to patch-up a broken heart and to extend a lifeline for those suffering from heart disease. It’s comforting to know that the regenerative abilities of FSTl1 will be explored in human models and will hopefully reach clinical trials.

Ke Wei (UCSD, Sanford-Burnham-Prebys) and Vahid Serpooshan (Stanford) were co-first authors on this study. The senior authors were Daniel Bernstein (Stanford), Mark Mercola (UCSD, Sanford-Burnham-Prebys), and Pilar Ruiz-Lozano (Stanford). Both Ke Wei and Mark Mercola received CIRM funding for this study.

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Related Links:

• Mark Mercola: differentiating stem cells into heart tissue (video)
• The secret to mending a broken heart (Stem Cellar Blog)
• Patching broken hearts: Stanford researchers regrow lost cells (Stanford Scope blog)
• Hearts build new muscle with this simple protein patch (SBP Science Beaker Blog)
• Stanford Press Release
• UCSD Press Release