Stem Cell Factor Promotes Cardiovascular Protection

This image shows an atherosclerotic lesion. Such lesions, which can rupture and cause heart attacks and strokes, appear to be stabilized by the pluripotency factor OCT4. [UVA School of Medicine]

Oct4—a gene essential to embryonic development—remains functional in adults, offering cardiovascular protection through the stabilization of atherosclerotic plaques. Essentially, Oct4 helps prevent heart attacks and strokes.

The finding is a surprise. While there had been hints that Oct4 could serve some function later in life, convincing evidence was lacking. Now that Oct4 has been shown to remain active in adult cells, influencing both the size and composition of atherosclerotic plaques, scientists are considering whether manipulating expression of this gene might help block age-related decline in the body’s ability to carry out repairs and heal wounds.

Even more general benefits are being envisaged. If adult cells are capable of varying degrees of plasticity—that is, if embryonic developmental factors can be reawakened—it may be possible to reinvigorate them, preventing some of the detrimental effects of aging. The implications for regenerative medicine could be profound.

These possibilities emerged from a study conducted by researchers based at the University of Virginia (UVA). These researchers, led by Gary K. Owens, Ph.D., found that Oct4 controls the movement of smooth muscle cells into protective fibrous “caps” inside the plaques—caps that make the plaques less likely to rupture. The researchers also have provided evidence that the gene promotes many changes in gene expression that are beneficial in stabilizing the plaques.

These observations, the scientists pointed out, mean that it may be possible to develop drugs or other therapeutic agents that target the Oct4 pathway as a means to reduce the incidence of heart attacks or stroke. “Our findings, said Olga A. Cherepanova, Ph.D., a senior research scientist in Dr. Owens' lab, “have major implications regarding possible novel therapeutic approaches for promoting stabilization of atherosclerotic plaques.”

Details of the UVA study appeared May 16 in the journal Nature Medicine, in an article entitled, “Activation of the Pluripotency Factor OCT4 in Smooth Muscle Cells Is Atheroprotective.” The article describes how the UVA scientists established a functional role for OCT4 in somatic cells—a significant first, given that earlier studies had not even firmly established whether the OCT4 pathway in somatic cells was active.

“Here we demonstrate that smooth muscle cell (SMC)-specific conditional knockout of Oct4 in Apoe^−/− mice resulted in increased lesion size and changes in lesion composition that are consistent with decreased plaque stability, including a thinner fibrous cap, increased necrotic core area, and increased intraplaque hemorrhage,” the article’s authors wrote. “Results of SMC-lineage-tracing studies showed that these effects were probably the result of marked reductions in SMC numbers within lesions and SMC investment within the fibrous cap, which may result from impaired SMC migration.”

When the researchers blocked the effect of Oct4 in mice, they thought the atherosclerotic plaques might become smaller, because of the reduced number of smooth muscle cells inside. Instead, the plaques grew larger, less stable, and more dangerous, stuffed with lipids, dead cells, and other damaging components.

While UVA's research has focused on how Oct4 offers cardiovascular protection, Dr. Owens and his colleagues believe the gene could also prove critical to the field of regenerative medicine, which investigates the growth and replacement of tissues and organs. The researchers believe that Oct4 and its family of target genes are activated in other somatic cells and play a key role in the cells’ ability to repair damage and heal wounds. Studies to test this are under way in Dr. Owens’ lab.

Oct4 is one of the “stem cell pluripotency factors” described by Shinya Yamanaka, M.D., Ph.D., for which he received the 2012 Nobel Prize. His lab and many others have shown that artificial overexpression of Oct4 within somatic cells grown in a lab dish is essential for reprogramming these cells into induced pluripotential stem cells, which can then develop into any cell type in the body or even an entire organism.

The UVA researchers suspect that at least some of the detrimental effects of aging, including the increased possibility of a plaque rupture, stem from a decrease in the body's ability to reactivate Oct4. “Finding a way to reactivate this pathway may have profound implications for health and aging,” Dr. Owens said. “We think this is just the tip of the iceberg for controlling plasticity of somatic cells, and this could impact many human diseases and the field of regenerative medicine. Who knows, this may end up being the ‘fountain-of-youth gene,’ a way to revitalize old and worn-out cells. Only time will tell.”