Smooth Muscle Cells from Reprogrammed Fibroblasts (p 1433)
Karamariti et al devise a new method for generating smooth muscle cells in vitro.
Smooth muscle cells (SMCs) are an essential component of blood vessels, and are thus required to engineer functional blood vessels in culture. Tissue engineers need a reliable and plentiful supply of SMCs. However, the methods currently used to obtain these cells - such as retrieving them from adult arteries and expanding them in vitro, or differentiating them from embryonic stem cells - can be inefficient, arduous, or both. Karamariti and colleagues propose a new approach, which involves direct reprogramming of fibroblasts into SMCs, by transfecting human fibroblasts with factors used for making induced pluripotent stem (iPS) cells. But instead of fully dedifferentiating the cells, they plated partially dedifferentiated cells, called PiPS, on collagen IV and induced them to become SMCs. The resulting cells exhibited SMC morphology, expressed SMC-specific markers and were capable of contracting like native SMCs. Through a careful monitoring of the reprogramming process, the researchers also discovered a novel factor, called DKK3, which activated the expression of an important SMC marker. The reprogrammed cells were then used with endothelial cells to build tissue-engineered vessels that functioned like their native counterparts when transplanted into mice. Overall, this new method could improve current approaches to vessel engineering and, as a result, help in the development of vessel grafts for patients.
Macrophage ABCA1/G1 Deletion Enhance Atherogenesis (p 1456)
Macrophages lacking cholesterol transporters make atherosclerosis much worse, say Westerterp et al.
High HDL levels in blood are associated with a lower risk of heart disease. The protective effects of HDL have been linked, in part, to its ability to promote cholesterol efflux from macrophages. However, it is unclear whether this efflux is indeed protective. Cholesterol efflux from macrophages is controlled by two transporter proteins, ABCA1 and ABCG1, so Westerterp and colleagues specifically deleted these proteins from the macrophages of atherosclerosis-prone mice. They found that this procedure led to an increase in the lipid content of the macrophages and increased atherogenesis. And while a deficiency in the cell’s cholesterol efflux did play a role in these changes, it was not the only contributing factor. In fact, in mice lacking ABCA1- and ABCG1 transporters in macrophages there was also an increase in monocytes and neutrophils, which led to increased inflammation in atherosclerotic plaques. It turned out that the ABCA1- and ABCG1-deficient macrophages were producing high levels of the cytokines G-CSF and M-CSF, which promote the production of neutrophils and monocytes, respectively. These findings suggest that strategies aimed at promoting cholesterol efflux will prevent the pro-inflammatory and pro-atherogenic potential of macrophages, and furthermore, that monitoring G-CSF and M-CSF levels could help assess the success of such strategies.
Antisense Inhibition of ApoC-III (p 1479)
Inhibition of ApoC-III by antisense RNA reduces triglyceride levels in both animals and humans.
Elevated levels of triglycerides in the blood are a well-known risk factor for coronary heart disease. And, therefore, reducing triglyceride levels might reduce that risk. To lower dangerously high triglyceride levels, doctors currently prescribe statins, niacin, fibrates and omega-3-fatty acids, but in many patients, achieving the recommended level is difficult. More effective remedies are therefore required. The glycoprotein ApoC-III is an important regulator of plasma triglyceride, and high levels of ApoC-III are associated with high levels of triglycerides. High ApoC-III levels have also been independently associated with metabolic disorder and type 2 diabetes. Thus, Graham and colleagues investigated lowering ApoC-III levels with antisense nucleotides directed against human and rodent ApoC-III mRNA. The antisense nucleotides successfully reduced plasma levels of both ApoC-III and triglycerides in rats, mice, transgenic mice carrying the human ApoC-III gene, rhesus monkeys, and most importantly, in healthy humans. Although this phase-I trial was performed in just 33 subjects, the results were significant and there were no adverse safety indications. The findings suggest that larger-scale phase-II clinical trials are warranted for this first-of-its-kind antisense ApoC-III therapy.
- © 2013 American Heart Association, Inc.