Scientists at UC Davis discover a way to help stem cells repair heart tissue

Researchers Phung Thai (left) and Padmini Sirish were part of a research team seeking stem cell solutions to heart failure care.  Image Credit: UC Davis

Repairing the permanent damage associated with a heart attack or long-term heart disease has been a challenge that scientists have been trying to tackle for a long time. Heart failure affects approximately 5.7 million people in the U.S and it is estimated that this number will increase to 9 million by the year 2030. At a biological level, the biggest challenge to overcome is cell death and thickening of muscles around the heart.

Recently, using stem cells to treat heart disease has shown some promise. However, little progress has been made in this area because the inflammation associated with heart disease decreases the chances of stem cell survival. Fortunately, Dr. Nipavan Chiamvimonvat and her team of researchers at UC Davis have found an enzyme inhibitor that may help stem cells repair damaged heart tissue.

Dr. Nipavan Chiamvimonvat
 Image Credit: UC Davis

The enzyme the team is looking at, known as soluble epoxide hydrolase (or sEH for short), is a known factor in joint and lung disease and is associated with inflammation. The inhibitor Dr. Chiamvimonvat and her team are studying closely is called TPPU and it is meant to block sEH.

In their study, the UC Davis team used human-induced pluripotent stem cells (hiPSCs), a kind of stem cell made by reprogramming skin or blood cells that then has the ability to form all cell types. In this case, the hiPSCs were turned into heart muscle cells.

To evaluate the effectiveness of TPPU, the team then induced heart attacks in six groups of mice. A group of these mice was treated with a combination of TPPU and the newly created heart muscle cells.  The team found that the mice treated with this combination approach had the best outcomes in terms of increased engraftment and survival of transplanted stem cells. Additionally, this group also had less heart muscle thickening and improved heart function. 

The next step for Dr. Chiamvimonvat and her team is to conduct more animal testing in order to obtain the data necessary to test this therapy in clinical trials.

In a press release, Dr. Chiamvimonvat discusses the importance of research and its impact on patients.

““It is my dream as a clinician and scientist to take the problems I see in the clinic to the lab for solutions that benefit our patients.”

The full study was published in Stem Cells Translational Medicine.

 

CIRM-Funded Scientists Test Recipe for Building New Muscles

When muscles get damaged due to disease or injury, the body activates its reserves—muscle stem cells that head to the injury site and mature into fully functioning muscle cells. But when the reserves are all used up, things get tricky.

Scientists at Sanford-Burnham may have uncovered the key to muscle repair.

Scientists at Sanford-Burnham may have uncovered the key to muscle repair.

This is especially the case for people living with muscle diseases, such as muscular dystrophy, in which the muscle degrades at a far faster rate than average and the body’s reserve stem cell supply becomes exhausted. With no more supply from which to draw new muscle cells, the muscles degrade further, resulting in the disease’s debilitating symptoms, such as progressive difficulty walking, running or speaking.

So, scientists have long tried to find a way to replenish the dwindling supply of muscle stem cells (called ‘satellite cells’), thus slowing—or even halting—muscle decay.

And now, researchers at the Sanford-Burnham Medical Research Institute have found a way to tweak the normal cycle, and boost the production of muscle cells even when supplies appear to be diminished. These findings, reported in the latest issue of Nature Medicine, offer an alternative treatment for the millions of people suffering not only from muscular dystrophy, but also other diseases that result in muscle decay—such as some forms of cancer and age-related diseases.

In this study, Sanford-Burnham researchers found that introducing a particular protein, called a STAT3 inhibitor, into the cycle of muscle-cell regeneration could boost the production of muscle cells—even after multiple rounds of repair that would otherwise render regeneration virtually impossible.

The STAT3 inhibitor, as its name suggests, works by ‘inhibiting,’ or effectively neutralizing, another protein called STAT3. Normally, STAT3 gets switched on in response to muscle injury, setting in motion a series of steps that replenishes muscle cells.

In experiments first in animal models of muscular dystrophy—and next in human cells in a petri dish—the team decided to modify how STAT3 functions. Instead of keeping STAT3 active, as would normally occur, the team introduced the STAT3 inhibitor at specific times during the muscle regeneration process. And in so doing, noticed a significant boost in muscle cell production. As Dr. Alessandra Sacco, the study’s senior author, stated in a news release:

“We’ve discovered that by timing the inhibition of STAT3—like an ‘on/off’ light switch—we can transiently expand the satellite cell population followed by their differentiation into mature cells.”

This approach to spurring muscle regeneration, which was funded in part by a CIRM training grant, is not only innovative, but offers new hope to a disease for which treatments have offered little. As Dr. Vittorio Sartorelli, deputy scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), stated:

“Currently, there is no cure to stop or reverse any form of muscle-wasting disorders—only medication and therapy that can slow the process. A treatment approach consisting of cyclic bursts of STAT3 inhibitors could potentially restore muscle mass and function in patients, and this would be a very significant breakthrough.”

Sacco and her colleagues are encouraged by these results, and plan to explore their findings in greater detail—hopefully moving towards clinical trials:

“Our next step is to see how long we can extend the cycling pattern, and test some of the STAT3 inhibitors currently in clinical trials for other indications such as cancer, as this could accelerate testing in humans.”