Changing your identity to protect others might sound like something reserved for comic book vigilantes, but a study led by researchers has found a select group of cells in artery walls do just that.
For these cells, the identity shift happens in a disease called atherosclerosis, which occurs when arteries get clogged by plaque, a buildup of fats, cholesterol and molecular particulate.
Plaque grows within the layers of tissue that form the artery, as opposed to inside the tube itself, causing the blood conduit to narrow. Too much plaque tears open the tissue, allowing the built-up gunk to flood the interior of the tube. That leads to a clot, which can cause artery blockage and often a heart attack.
In people with atherosclerosis, cells that make up the artery wall transform and invade the area containing the plaque, or lesion, and form something called a fibrous cap, which acts kind of like a lid to prevent the plaque from bursting into the artery. Now, the researchers have characterized the identity of these transformed cells, giving key insights into something called plaque stability, which determines the likelihood of a plaque bursting. The more robust the fibrous cap, the more stable the plaque and the less likely it is to rupture.
The team has also pinpointed a gene that seems to be behind the cells' transformation. What's more, when they looked at population wide genomic data, they saw that individuals who had more activity in this particular gene were at a decreased risk for heart attack.
"Logically, it makes sense -- the more cells that help form the fibrous cap, the stronger the protection against plaque rupture and therefore the less risk of a heart attack," said the senior author.
A paper describing the details of the study will be published in Nature Medicine.
Under healthy conditions, the smooth muscle cells that make up the wall of arteries control the vessel's dilation, expanding and contracting to regulate blood flow and blood pressure. But when plaque in the artery starts to build, smooth muscle cells begin to shift.
The cells actually move toward the plaque lesion, the author said. The genes that make the smooth muscle cells begin to shut off and, in their place, new genes turn on. Then, like Clark Kent to Superman, the smooth muscle cells ditch their everyday identity for a heroic version of themselves -- the fibromyocyte, similar to a fibroblast, a cell type known for its role in connective tissue and collagen production. The fibromyocytes then form a protective cap over the cholesterol, fat and molecular debris that compose arterial plaque.
"It's kind of like a scab over a wound," the senior author said. "Only in this case, the scab also keeps the plaque stable."
Researchers have known that smooth muscle cells reinvent themselves during atherosclerosis, but it wasn't clear exactly what their new identity was. Scientists thought these cells could have a beneficial role, but also suspected they could transform into dysfunctional immune cells that promote inflammation and worsen the condition.
To figure out the smooth muscle cells' intentions, the authors used an experimental technique in mice called lineage tracing, which allowed the scientists to track the whereabouts of specific cells and cells derived from those cells. The group labeled arterial smooth muscle cells in the mice with a special chemical that turns the cells red under a microscope. Then, after inducing a mouse version of atherosclerosis, they checked the arteries for signs of smooth muscle cell movement. They observed that some of the red-labeled smooth muscle cells had moved into the plaque from their original homes in the artery.
The authors then profiled all the cells in the artery, analyzed the collection of cells -- immune, smooth muscle, fibromyocyte and more -- and ran gene expression analyses to see which genes were "on" in each individual cell. According to the gene expression analysis, the red-labeled smooth muscle cells that migrated to the plaque were sporting a new look.
"These cells exhibited a sort of swap: Patterns of gene activity that track with smooth muscle cells decreased, and activity of genes that give rise to fibromyocytes increased," the senior author said. "The data allowed us to, beyond a shadow of a doubt, characterize these particular cells in the plaque as smooth muscle cells that have turned into fibromyocytes." Remarkably, the researchers found no evidence that smooth muscle cells transformed into plaque-destabilizing immune cells, resolving a long-standing question in the field.
Next, the researchers used a form of computer modeling to bridge mouse biology to humans. They took tissue samples from human patients with atherosclerosis who'd received heart transplants. The scientists analyzed cells from the human arteries with the same single-cell gene expression method used in the mouse tissue.
With data from both human and mouse atherosclerotic tissue, the computer model accurately identified cell types, regardless of species. Importantly, the researchers found the same phenomenon occurring in the human arteries: Smooth muscle cells were also transforming into fibromyocytes during human disease.
The researchers went even one step further, identifying the gene that seems to drive the transition from smooth muscle cell to fibromyocyte during atherosclerosis. The earlier work from the lab had identified one particular gene, TCF21, that was associated with a person's risk for coronary artery disease.
So they tested that theory in a mouse model of atherosclerosis, disabling the TCF21 gene to see if it exacerbated the disease. The authors saw that mice without TCF21 formed fewer fibromyocytes overall, fewer fibromyocyte cells in the plaque and a less-sturdy fibrous cap.
The authors said that TCF21 could likely help guide them toward a new therapy for coronary artery disease. But before taking steps in that direction, there's still more to understand about TCF21 and how it mediates this transformation at the molecular level, they said. "Now we have good evidence that the ability for smooth muscle cells to undergo this transformation to fibromyocytes is important to protect against clinically significant coronary disease, but the timing and extent of this transformation is likely also important," the lead said.
Smooth muscle cells on the artery wall changes identity to protect against rupture in atherosclerosis
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