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A Distinct Population of Smooth Muscle Cells is Associated with Vascular Disease


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Posted 08 November 2018 - 09:36 PM


Researchers have identified a marker for a small population of smooth muscle cells in blood vessel walls that show up in larger numbers in cases of vascular disease, such as atherosclerosis. These cells may be dysfunctional in the sense that they (a) appear to be involved in inflammatory signaling and (b) lose the normal behavior of smooth muscle tissue. My first thought on reading the abstract of the paper was that this may be a senescent population, as inflammation and disruption of tissue function are quite characteristic of the bad behavior of senescent cells. On closer reading that sounds less likely, however. These may well be cells that are engaged in repair and regrowth activities, which also tend to involve at least short term inflammation alongside significant changes in cell activities.

Are these cells harmful, or are they responding in a beneficial way? That may depend on context; it might be the case that they are initially beneficial, but in the later stages of disease progression they become a problem, and contribute to the disease state. The discovery of a marker allows technologies such as the Oisin Biotechnologies suicide gene therapy platform to target these cells for destruction. Evaluating the outcome in mice is the fastest way to determine whether or not the cells are harmful, and whether or not this varies with disease progression. This is the case for the removal of a broad range of other potentially harmful cell populations found in older individuals. Most of these projects are easy to describe, and all of the necessary preliminary work of identifying the cells has been accomplished, but still no-one is even thinking about undertaking the work. The challenge here is that there is too little philanthropy, too few entrepreneurs, and too little venture funding to carry out anywhere as much as many projects as should be underway right now.

Observation of blood vessel cells changing function could lead to early detection of blocked arteries

The muscle cells that line the blood vessels have long been known to multi-task. While their main function is pumping blood through the body, they are also involved in patching up injuries in the blood vessels. Overzealous switching of these cells from the pumping to the repair mode can lead to atherosclerosis, resulting in the formation of plaques in the blood vessels that block the blood flow. Using state-of-the art genomics technologies, an interdisciplinary team of researchers has caught a tiny number of vascular muscle cells in mouse blood vessels in the act of switching and described their molecular properties. The researchers used an innovative methodology known as single-cell RNA-sequencing, which allows them to track the activity of most genes in the genome in hundreds of individual vascular muscle cells.

"We knew that although these cells in healthy tissues look similar to each other, they are actually quite a mixed bag at the molecular level. However, when we got the results, a very small number of cells in the vessel really stood out. These cells lost the activity of typical muscle cell genes to various degrees, and instead expressed a gene called that is best known to mark stem cells, the body's master cells." Knowing the molecular profile of these unusual cells has made it possible to study their behaviour in disease. Researchers have confirmed that these cells become much more numerous in damaged blood vessels and in atherosclerotic plaques, as would be expected from switching cells. "Theoretically, seeing an increase in the numbers of switching cells in otherwise healthy vessels should raise an alarm. Likewise, knowing the molecular features of these cells may help selectively target them with specific drugs."

Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels

Vascular smooth muscle cells (VSMCs) show pronounced heterogeneity across and within vascular beds, with direct implications for their function in injury response and atherosclerosis. Here we combine single-cell transcriptomics with lineage tracing to examine VSMC heterogeneity in healthy mouse vessels. The transcriptional profiles of single VSMCs consistently reflect their region-specific developmental history and show heterogeneous expression of vascular disease-associated genes involved in inflammation, adhesion, and migration.

We detect a rare population of VSMC-lineage cells that express the multipotent progenitor marker Sca1, progressively downregulate contractile VSMC genes and upregulate genes associated with VSMC response to inflammation and growth factors. We find that Sca1 upregulation is a hallmark of VSMCs undergoing phenotypic switching in vitro and in vivo, and reveal an equivalent population of Sca1-positive VSMC-lineage cells in atherosclerotic plaques. Together, our analyses identify disease-relevant transcriptional signatures in VSMC-lineage cells in healthy blood vessels, with implications for disease susceptibility, diagnosis, and prevention.


View the full article at FightAging




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