Fibroblast Growth Factor 9 Helps Form Vasoreactive Vessels
University of Western Ontario ♦ Published in Nature Biotechnology, April 17, 2011
Some interesting findings from the University of Western Ontario could have implications for future angiogenesis therapies and tissue engineering approaches to the treatment of vascular disease. Researchers discovered that fibroblast growth factor 9 (FGF9), an angiogenic growth factor, contributes to the development of vasoreactive blood vessels. Two primary processes must occur within implants to produce functional grafts. Firstly, endothelial cells must be stimulated to produce angiogenic sprouts, and secondly, these sprouts must be muscularized by being wrapped in smooth muscle cells. The latter of these two processes is crucial for vasoreactivity — the ability of vessels to alter the luminal diameter to control the flow of blood into capillary beds. Fibroblast growth factor 2 (FGF2) has been shown to stimulate endothelial cells to form angiogenic sprouts, but its utility in producing functioning grafts has been limited because it does not stimulate the formation of cords of smooth muscle cells that allow for vasoreactivity. FGF9, on the other hand, fails to produce angiogenic sprouts but seems to direct mesenchymal cells to produce the muscle necessary for control over luminal diameter. Researchers show that delivering FGF9 to implants produces stable, durable, and vasoresponsive blood vessels that can remain physiologically competent for at least a year. This research challenges the notion that endothelial cells must be targeted for vascular repair, and suggests that targeting mesenchymal cells may be the more crucial consideration in developing angiogenesis therapies. It will likely be a combination of targeting both cell types and using a variety of angiogenic growth factors, including FGF2 and FGF9.
B Cells Drive Insulin Resistance in Animal Model
Stanford University ♦ University of Toronto ♦ Duke University Medical Center
Published in Nature Medicine, April 17, 2011
One of the key drivers of insulin resistance and glucose intolerance is chronic inflammation of the visceral adipose tissue (VAT). Inflammation of VAT is caused by the infiltration of macrophages that produce proinflammatory cytokines, and infiltration by T cells that also trigger inflammatory mechanisms. It now looks like B cells are in the mix as well, exhibiting a pathogenic role in the development of metabolic abnormalities. Using a knockout mouse model that fails to produce mature B cells, researchers showed that mice without B cells had lower fasting glucose and greater glucose tolerance than wild type mice. Knockout mice also had reduced fasting insulin and improved insulin sensitivity, and fewer proinflammatory macrophages in VAT compared to normal animals. Investigation into the mechanisms in which B cells promote metabolic abnormality led to the finding that B cells activate T cells through the presentation of an MHC complex, and that this was linked to glucose tolerance. In addition to modulating T cells, B cells also release IgG antibodies that regulate immune function. It was found that IgG in VAT induced a considerable decline in glucose tolerance, the effects of which were associated with decreased fasting insulin, one of the hallmarks of insulin resistance. Treating mice with CD20, a B cell-depleting antibody, attenuated disease, while transfer of IgG antibodies from mice with diet-induced obesity to normal mice rapidly induced glucose intolerance.