Researchers at the University of Buffalo have discovered that stem cells are involved in the inflammation that promotes atherosclerosis.
Atherosclerosis or hardening of the arteries occurs when fat, cholesterol, and other substances build up in the walls of arteries and form hard structures called plaques. With the passage of time, these plaques can grow and block the arteries, depriving tissues of oxygen and nutrition.
High serum cholesterol levels have been unequivocally linked to an increased risk of arteriosclerosis. However, the deposition of cholesterol and other molecules underneath the inner layer (intima) of arteries requires a phenomenon known as inflammation. Inflammation occurs in response to tissue damage and it involves the dilation of blood vessels, increased blood flow the damaged area, the recruitment of white blood cells to the area, and increased heart, volume, and pain at the area in question. Increased inflammation within blood vessels damages the intimal layer and allows the deposition of cholesterol and other molecules underneath it to form an atheroma or a plaque.
The stem cell link to atherosclerosis is that the bone marrow-based stem cells that make our blood cells (hematopoietic stem/progenitor cells or HSPCs) ramp up their production of white blood cells in response to increased serum cholesterol levels.
Thomas Cimato, assistant professor in the Department of Medicine in the UB School of Medicine and Biomedical Sciences, said of his publication, “Our research opens up a potential new approach to preventing heart attack and stroke, by focusing on interactions between cholesterol and the HSPCs. Cimto also suggested that these findings could lead to the development of a useful therapy in combination with statins, or a treatment in place of statins for those who cannot tolerate statins.
In Cimato’s study, high cholesterol levels were shown to cause increases in the levels of interleukin -17 (IL-17). IL-17 is a cytokine that recruits monocytes and neutrophils to the site of inflammation. IL-17 boosts levels of granulocyte colony stimulating factor (GCSF), which is a factor that induces the release of HSPCs from the bone marrow to the peripheral circulation.
Cimato also found that statin drugs reduce the number of HSPCs in circulation, but not all patients responded similarly to statins. “We’ve extrapolated to humans what other scientists previously found in mice about the interactions between LDL, cholesterol, and these HSPCs,” said Cimato.
In order to transport cholesterol through the bloodstream, cells must construct a vehicle into which the cholesterol is packaged. Cholesterol does not readily dissolve in water. Therefore, packaging cholesterol into lipoprotein particles allows for its transport around the cell. Cell use cholesterol to vary the fluidity of their membranes, and to synthesize steroid hormones. Once cholesterol is absorbed from the diet, the cells of the small intestine package cholesterol and fat into a particle known as a chylomicron.
Chylomicrons are released by the small intestinal cells and they travel to the liver. In the liver, chylomicrons are disassembled and the cholesterol is packaged into a particle known as a very-low density lipoprotein particle (VLDL). After its release and sojourning through the bloodstream, the VLDL looses some surface proteins and is depleted of its fat and becomes known as a low-density lipoprotein or LDL particle. While these particles sojourn through the bloodstream, they release fat for tissues to use as an energy source.
LDL particles are gradually removed from circulation. If they build up to high concentrations, they can be taken up by a wandering white blood cell known as a macrophage. If these macrophages take up too much LDL, they can become a foam cell. Foams cells can become lodged underneath the intimal layer of blood vessels when inflammation occurs inside blood vessels, and this is the cause of atherosclerosis.
Increased LDL levels in mice have been shown to stimulate the release of HSPCs from bone marrow and accelerate the differentiation of these cells into white blood cells (neutrophils and monocytes) that participate in inflammation.
Mice do not regulate their cholesterol levels in the same way humans do. Cimato commented, “mice used for atherosclerosis studies have very low total cholesterol levels at baseline. We feed then very high fat diets in order to study high cholesterol but it isn’t easy to interpret what the levels in mice will mean in humans and you don’t know if extrapolating to humans will be valid.”
Therefore, in order to properly model cholesterol regulation in their human subjects, Cimato had them take statins for a two-week period followed by one-month intervals when they were off the drugs. “We modeled the mechanism of how LDL cholesterol affects stem cell mobilization in humans,” said Cimato.
The experiments showed that increased LDL levels tightly correlated with IL-17 levels.
Secondly, blood LDL levels also correlated with GCSF levels.
Finally, increasing GCSF levels led to higher levels of circulating HSPCs.
These circulating HSPCs increase the numbers of neutrophils, monocytes, and macrophages that are involved in the formation of plaque and atherosclerosis.
The next step is to determine if HSPCs, like LDL cholesterol levels are connected to stroke, cardiovascular disease and heart attacks.