Mesenchymal Stem Cell Transplantation Improves Atherosclerotic Lesions

Several animal studies have shown that transplantation of mesenchymal stem cells from several different sources is beneficial in myocardial infarction and hind limb ischemic. However, can these cells improved atherosclerosis, otherwise known as hardening of the arteries?

Shih-Chieh Hung and colleagues from National Yang-Ming University in Taipei, Taiwan tested this very hypothesis.

Hung and others used to lines of experimentation to address this question. First, they used cultured endothelial cells that had been treated with oxidized low-density lipoprotein particles. Secondly, they fed mice mutant for ApoE-deficient a high-fat diet.  ApoE-deficient humans and mice develop atherosclerotic plaques rather quickly.

In the cultured endothelial cells, oxidized LDL turned off the production of nitric oxide (NO). NO is a signaling molecule produced by several cell types, but in particular, endothelial cells use NO to dilate blood vessels. NO also is a good signal of endothelial health. Therefore, when oxidized LDL causes cultured endothelial to decrease NO production, it is affecting endothelial cell health. However, when cultured endothelial cells that had been treated with oxidized LDL were cocultured with mesenchymal stem cells, NO production and the enzymes that synthesize NO increased precipitously. Thus in a cultured system, MSCs have the ability to prevent the deleterious of oxidized LDL.

In ApoE-deficient mice fed a high fat diet, the arteries of the mice showed extensive plaque formation. However, if these animals were implanted with bone-marrow-derived mesenchymal stem cells, plaque formation was greatly decreased. Further work showed that a protein secreted by mesenchymal stem cells called macrophage inflammatory protein-2 (MIP-2) was responsible for these ameliorative effects. If MIP-2 was applied without mesenchymal stem cells, plaque formation was limited, and if antibodies that neutralize MIP-2 were co-administered with mesenchymal stem cells, the cells failed to reduced plaque formation.

Thus, this interesting study shows that transplantation of mesenchymal stem cells can limit plaque formation in atherosclerotic animals and they do this through secretion of MIP-2. Secondly, mesenchymal stem cells can improve the health of endothelial cells, which are the cells that form the inner layer of blood vessels, which are so adversely affected by atherosclerosis. By utilizing the encore of proteins secreted by mesenchymal stem cells, scientists should be able to develop a cocktail of proteins that can ameliorate atherosclerosis in human patients.

First Patient Treated in Study that Tests Stem Cell-Gene Combo to Repair Heart Damage

The first patient has been treated in a groundbreaking medical trial in Ottawa, Canada, that uses a combination of stem cells and genes to repair tissue damaged by a heart attack. The first test subject is a woman who suffered a severe heart attack in July and was treated by the research team at the Ottawa Hospital Research Institute (OHRI). Her heart had stopped beating before she was resuscitated, which caused major damage to her cardiac muscle.

The therapy involves injecting a patient’s own stem cells into their heart to help fix damaged areas. However, the OHRI team, led by cardiologist Duncan Stewart, M.D., took the technique one step further by combining the stem cell treatment with gene therapy.

“Stem cells are stimulating the repair. That’s what they’re there to do,” Dr. Stewart said in an interview. “But what we’ve learned is that the regenerative activity of the stem cells in these patients with heart disease is very low, compared to younger, healthy patients.”

Stewart and his colleagues will supply the stem cells with extra copies of a particular gene in an attempt to restore some of that regenerative capacity. The gene in question encodes an enzyme called endothelial nitric oxide synthase (eNOS). Nitric oxide is a small, gaseous molecule that is made from the amino acid arginine by the enzyme nitric oxide synthase. Nitric oxide or NO signals to smooth muscle cells that surround blood vessels to relax, which causes blood vessels to dilate and this increases blood flow. In the damaged heart, NO also helps build up new blood vessels, which increase healing of the cardiac muscle. Steward added, “That, we think, is the key element. We really think it’s the genetically enhanced cells that will provide the advantage.”

Nitric oxide synthesis

The study will eventually involve 100 patients who have suffered severe heart attacks in Ottawa, Toronto and Montreal.