

The findings, published Wednesday in the journal Nature Communications, go against the prevailing theory on the cause of heart disease - that the smooth muscle cells that line blood vessels become damaged over time and are triggered to proliferate. Those smooth muscle cells were thought to build up like scar tissue and cause the blood vessels to become narrow or brittle.

The new theory suggests that the smooth muscle cells found in the blood vessel walls aren't to blame, but rather a small cluster of stem cells is. It's those stem cells that proliferate and cause damage, and they should be the target of drug therapies to treat, and potentially cure, heart disease, the UC Berkeley scientists say.

"We call them sleeping beauty or sleeping evil cells, because they don't do anything when they're dormant. The stem cells stay quiescent for decades before they start to grow and they make the blood vessels harden," said senior author Song Li, a bioengineering professor at UC Berkeley and a researcher at the Berkeley Stem Cell Center.


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"These stem cells are probably less than 5 percent of the cells in the blood vessel when they're dormant," Li said. "But they can dominate. They can become the major cell."

Root of it all

Li and his team still believe that smooth muscle cells are to blame for much of the damage in the blood vessels. What's changed is where those cells come from.

Scientists have known for decades that the blood vessel damage associated with heart disease is caused by a buildup of smooth muscle cells. Those clumps of cells cause the blood vessel to become dangerously narrow, hindering the flow of blood, or they become brittle clots that break off and block vessels entirely.

When the blood flow is slowed or stopped completely, it can cause strokes or heart attacks, depending on the location of the blockage. Strokes and heart attacks are among the most common causes of death in the United States.

The stem cells, which Li and his team have named multipotent vascular stem cells, remained undiscovered because so few of them exist when they're dormant. It didn't help that after they become activated, they look very similar to the smooth muscle cells that scientists have long thought were the culprit in heart disease.

The prevailing theory has been that damage to the blood vessel caused the smooth muscle cells in the vessel walls to "de-differentiate," or revert to an earlier stage of development that allows them to reproduce and build the scar-like tissue. But there was no proof of it, Li and others noted.

Li set about looking. He found that there were indeed buildups of smooth muscle cells, but those cells weren't from the same lineage as the smooth muscle cells in the blood vessel walls. That meant they came from a different source.

Morphing cells

Using tools for tracking cell lineage, Li traced those smooth muscle cells back to the multipotent vascular stem cells. Those stem cells, he found, are able to develop into several different kinds of cells - including smooth muscle cells.

"These findings shift the paradigm," said Dr. Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease at UCSF, who provided mouse tissue samples to the UC Berkeley scientists but was not involved in the research.

"If the new data holds up, the target for treating vascular disease may be very different than what we've been aiming at," Srivastava said. "Maybe the reason we've met with limited success in treating heart disease is because we've been going after the wrong target."

Srivastava noted that the UC Berkeley research will need to be reproduced by other scientists before it can replace the prevailing theories. And while Li and his team found the multipotent vascular stem cells in human carotid arteries, they did most of their research on mouse, not human, tissue.

Li said that, aside from reproducing his findings, the next step may be developing cellular lines of the stem cells to test possible drug therapies. Scientists will look for ways to keep the stem cells dormant, for example, or possibly just keep them from turning into the smooth muscle cells that seem to cause the most damage.

The stem cells, he said, were also capable of becoming nerve, cartilage, bone and fat cells. Further research may show that the stem cells' ability to become cartilage and bone cells explains why damaged blood vessels can become hard and brittle - not unlike bone.

Today's treatments

The therapies currently used to treat heart disease, Li said, often attack just the symptoms - statins to lower the cholesterol that causes plaque buildup in the arteries, for example, or stents to widen blood vessels and keep them open. Most current therapies haven't been nearly as successful at treating heart disease as doctors would like.

The stem cells may be a target that's at the root of the cause, rather than a symptom, Li said.

Dr. Cesar Molina, medical director of the South Asian Heart Center at El Camino Hospital in Mountain View, said the stem cell discovery was "eye opening," but he cautioned that even if further research proves valuable, doctors are a long way from finding a cure for heart disease.

"This paper shows how difficult it is to deal with this very complex problem," said Molina, who chairs My Life Check in Silicon Valley, an American Heart Association program to help people determine their risk of developing heart disease and take steps to prevent it.

"We forget, and this is really important as we keep making these discoveries, that many of these conditions are caused by our lifestyle," Molina said. "They say an ounce of prevention is worth a pound of cure. But that's all a lie, because there's no cure. We want to work on the prevention of cardiovascular disease first."
