By Amanda Chase, PhD
June 16, 2020

Heart disease is the leading cause of death in the US for both men and women. Heart disease, or cardiovascular disease, generally involves narrowed or blocked blood vessels that ultimately restrict blood flow, and thus decrease oxygen and nutrient delivery to the body. The narrowing of vessels is caused by a build-up of fats and cholesterol, as well as inflammatory cells, that result in plaque formation, a process called atherosclerosis. Risk factors for atherosclerosis include high cholesterol, high blood pressure, smoking, and diabetes, among others. Current therapies target the risk factors (e.g., statin to decrease lipids, recommendation to stop smoking, and suggestion to maintain a healthy lifestyle). To date, there are no therapies directly targeting the cells responsible for plaque formation, which could significantly reduce cardiovascular risk beyond what is possible with current therapies.

A team of researchers, led by first author Ying Wang, PhD, and senior author Nicholas Leeper, MD, from Stanford University Department of Surgery and Cardiovascular Institute, aimed to address this unmet need. Previous work has suggested that vascular smooth muscle cells (SMCs), which line the blood vessels, can lose specialized characteristics (undergo ‘phenotype switching’) and can express stem cell markers. These cells, which rapidly divide and undergo clonal expansion, give rise to the majority of cells within the plaque. These cells could be a therapeutic target, similar to the field of oncology and the targeting of cancer stem cells. The therapeutic potential of these atherosclerotic stem cells relies on an understanding how the cell promotes inflammation for plaque formation and how it escapes the immune system. In a paper recently published in PNAS, Dr. Leeper and his team were able to address those questions to propose a novel approach for lessening plaque burden.

In a sophisticated series of experiments, mice were used to observe and track SMC fate, confirming that these cells can de-differentiate and express certain stem cell markers. Furthermore, human samples showed that the findings have clinical relevance. The researchers show that the cells have a survival advantage for two reasons: (1) they have an abnormally high rate of cell division, meaning that significantly higher numbers of cells can be generated, and (2) they are able to escape the body’s immune response. Together, this results in an overabundance of cells and plaque formation.

One arm of the body’s immune response relies on macrophages, cells that “eat” debris and damaged or old cells. Macrophages should, therefore, prevent expansion of cells (i.e., atherosclerotic stem cells). Interestingly, Dr. Leeper and his team found that a defect in macrophages makes them unable to correctly see the atherosclerotic stem cells as a threat, and they also found that there is an increase in the presence of a “don’t eat me” signal (CD47) on the cells, providing further protection from macrophages. Combined, this results in a survival advantage for atherosclerotic stem cells, explaining their ability to form plaques. Importantly, the CD47 “don’t eat me” signal is a new target for a cancer treatment, as a large amount is found on the surface of nearly every cancer cell, similar to what was shown in this publication for atherosclerotic stem cells. Indeed, Dr. Leeper and his team were able to show that blocking CD47 restored macrophage function, reduced the continued expansion of the number of cells, and resulted in a decreased chance of plaque formation. The results of this intriguing work suggest, therefore, that therapies targeting CD47 could provide treatment to reduce plaque formation by directly treating cells responsible for forming plaques and reducing cardiovascular risk to a level not possible with current methods.

Other Stanford Cardiovascular Institute affiliated authors are Vivek Nanda, Abhiram Rao, and James Priest. Other Stanford affiliated authors are Dan Direnzo, Jianqin Ye, Sophia Xiao, Yoko Kojima, Kathryn Howe, Kai-Uwe Jarr, Alyssa Flores, Pavlos Tsantilas, Noah Tsao, Anne Eberhard, and Irving Weissman.