A Link Between Stem Cells, Atherosclerosis, and Cholesterol


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.

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

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.

IL-17 and cholesterol levels

Secondly, blood LDL levels also correlated with GCSF levels.

LDL levels and GCSF levels

Finally, increasing GCSF levels led to higher levels of circulating HSPCs.

CD34 cells and G-CSF levels

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.

Stem Cells and LDL Play a Role in Atherosclerosis


Researchers at the University at Buffalo have discovered a new understanding of atherosclerosis in humans that include a key role for stem cells that promote inflammation.

Published in the journal PLOS One, this work extends to humans previous findings in lab animals by researchers at Columbia University that showed that high levels of LDL (“bad”) cholesterol promote atherosclerosis by stimulating production of hematopoietic stem/progenitor cells (HSPC’s).

“Our research opens up a potential new approach to preventing heart attack and stroke, by focusing on interactions between cholesterol and the HSPCs,” says Thomas Cimato, lead author on the PLOS One paper and assistant professor in the Department of Medicine in the UB School of Medicine and Biomedical Sciences.

Cimato noted that the role of stem cells in atherosclerosis could lead to the development of a useful therapy in combination with statins or to a novel therapy that could be used in place of statins for those individuals who cannot tolerate them.

In humans, high total cholesterol recruits stem cells from the bone marrow into the bloodstream. The cytokine IL-17, which has been implicated in many chronic inflammatory diseases, including atherosclerosis, is responsible for the recruitment of HSPCs. IL-17 boosts levels of granulocyte colony stimulating factor (GCSF), which induces the release of stem cells from the bone marrow.

According to Cimato, they observed that statins reduce the levels of HSPCs in the blood but not every subject responded similarly. “We’ve extrapolated to humans what other scientists previously found in mice about the interactions between LDL cholesterol and these HSPCs,” explains Cimato.

The fact that a finding in laboratory animals holds true for humans is noteworthy, adds Cimato. “This is especially true with cholesterol studies,” he says, “because mice used for atherosclerosis studies have very low total cholesterol levels at baseline. We feed them very high fat diets in order to study high cholesterol but it isn’t [sic] easy to interpret what the levels in mice will mean in humans and you don’t know if extrapolating to humans will be valid.”

Cimato added that the LDL concentrations in the blood of mice in their studies is much higher than what is found in patients who come to the hospital with a heart attack or stroke.

“The fact that this connection between stem cells and LDL cholesterol in the blood that was found in mice also turns out to be true in humans is quite remarkable,” he says.

Cimato explains that making the jump from rodents with very high LDL cholesterol to humans required some creative steps, such as the manipulation of the LDL cholesterol levels of subjects through the use of three different kinds of statins.

The study involved monitoring for about a year a dozen people without known coronary artery disease who were on the statins for two-week periods separated by one-month intervals when they were off the drugs.

“We modeled the mechanism of how LDL cholesterol affects stem cell mobilization in humans,” says Cimato.

Cimato and his group found that LDL cholesterol modulates the levels of stem cells that form neutrophils, monocytes and macrophages, the primary cell types involved in the formation of plaque and atherosclerosis.

The next step, he says, is to find out if HSPCs, like LDL cholesterol levels, are connected to cardiovascular events, such as heart attack and stroke.

Cholesterol Derivatives Push Neural Stem Cells to Become Cells for Parkinson’s Disease Treatments


When we hear the word cholesterol we often have very negative thoughts of clogged arteries, heart attacks and strokes. However, cholesterol serves several vital roles in our bodies. It regulates the fluidity of the membranes of our cells, serves as a precursor for the synthesis of steroid hormones (such as estrogen, testosterone, cortisol and others), and is an important signaling molecule for several biological processes. Therefore. cholesterol is not all bad. Cholesterol when we get too much of it and our bodies handle the excess cholesterol poorly. Then wandering cells called macrophages have to mop up the excess cholesterol, but it makes them sick, and they get lost underneath the inner layers of blood vessels. That, however, is for another blog post.

In the present study, scientist from Karolinska Institutet in Sweden have identified two molecules, both of which are derivatives of cholesterol, that can help turn brain cells into the kind of cells that die during Parkinson’s disease. This finding might be useful for producing large quantities of neurons in the laboratory for therapeutic purposes.

As I have blogged before Parkinson’s disease results from the death of midbrain neurons that use the neurotransmitter dopamine. Because these midbrain neurons project to, in part, regions of the brain involved in voluntary movement, the death of the dopamine-using neurons in the midbain produces pronounced defects in voluntary movement and resting stability. Several experiment in humans and laboratory animals have definitively shown that cell transplantation experiments can improve the symptoms of patients with Parkinson’s disease. Therefore, cultivating and growing dopamine-using neurons in the laboratory is of cardinal importance in the treatment of this devastating disease.

Workers in the laboratory of Ernest Arenas investigated molecules known to play a role in the differentiation of midbrain neurons. They discovered that a group of receptors collectively known as “liver X receptors” or LXRs are necessary for making ventral midbrain neurons from neural stem cells. However, they were unsure what molecules bound to the LXRs in order to activate them.

Enter cholesterol stage right. By subjecting LXRs to a cocktail of molecules from living organisms and analyzing by means of mass spectrometry, they discovered that two molecules, cholic acid (a bile salt), and 24,25-EC, both of which are derivatives of cholesterol, bind to LXR and activate it.

Cholesterol
Cholesterol
Cholic Acid
Cholic Acid

24,25-Epoxycholesterol24,25-Epoxycholesterol

Cholic acid binds to LXR and stimulates the neural stem cells to form a group of midbrain cells known as the “red nucleus.” The red nucleus receives signals from several different parts of the brain to coordinate the movements of several different parts of the body. The other molecule, 24,25-EC binds to LXR and induces the formation of dopamine-using midbrain neurons – the ones that die off during Parkinson’s disease.

These data could open the possibility that cholesterol derivatives can be used to produce dopamine-using neurons from neural stem cells to treat Parkinson’s disease.

Ernest Arenas, professor of stem cell neurobiology in the department of biochemistry and biophysics, who led this study said: “We are familiar with the idea of cholesterol as a fuel for cells, and we know that it is harmful for humans to consume too much cholesterol. What we have shown now is that cholesterol has several functions, and that it is involved in extremely important decisions for neurons. Derivatives of cholesterol control the production of new neurons in the developing brain. When such a decision has been taken, cholesterol aids in the construction of these new cells, and in their survival. Thus cholesterol is extremely important for the body, and in particular for the development and function of the brain.”