This series showcases video summaries of new findings published in the Journal of Clinical Investigation. This format allows authors to to provide a personally guided tour of their results and makes the research more accessible to a broad readership. The JCI accepts videos from authors of recently accepted manuscripts. Instructions can be found on the Author's Take Guidelines page.
Platelet accumulation and coagulation are key processes required to stop bleeding following blood vessel injury. Plasma fibronectin, which circulates freely in the blood, contains collagen, fibrin, and integrin binding sites and is well poised to contribute to hemostasis. In this episode, Heyu Ni and colleagues demonstrate that plasma fibronectin is not only vital to control bleeding in fibrin-deficient mice and in mice given anticoagulants, but may also inhibit thrombosis away from the site of injury. Together, the results from this study suggest that plasma fibronectin has therapeutic potential to control bleeding and modulate thrombosis.
There is a strong association between obesity and type 2 diabetes (T2D); however, the majority of obese individuals do not develop T2D, supporting that genetic predisposition is an important component of the disease. Alan Attie and colleagues previously revealed that polymorphisms in the Sorcs1 gene are associated with diabetes in obese mice. In this episode, Alan Attie, Angie Oler, and Melkam Kebede discuss their current study, which demonstrates that SORCS1 is required to replenish insulin secretory granules. Although obese Sorcs1-defient mice developed severe T2D, insulin secretion in response to a single glucose challenge did not appear dysfunctional in these animals. However, repeated challenge of islets isolated from Sorcs1-deficient mice resulted in loss of secretory granule production and insulin content. These results suggest that some insulin secretion defects in patients may not be revealed by a single secretagogue challenge.
Muscle satellite cells are a rare regenerative population in adult skeletal muscle and have potential to repair damaged muscle tissue. In this episode, Simone Spuler and colleagues demonstrate that satellite cells can be successfully expanded from human adult muscle biopsies in culture and transplantation of satellite cell-containing human muscle fiber fragments into irradiated mice restores damaged muscle tissue. Isolated muscle fibers could be stored in the cold for a period of time and still retain the ability to engraft and regenerate muscle. Moreover, Spuler and colleague determined that adult-derived satellite cells could be genetically manipulated with Sleeping Beauty transposon–mediated gene transfer. Together, this study suggests that adult human muscle satellite cells have potential as a gene therapy tool for treating muscular dystrophies.
Age-related declines in immune function result in enhanced susceptibility to infection and decreased vaccine efficacy. While aged immune cells exhibit signs of cellular senescence, such as a reduced proliferative capacity, many maintain effector function. In this episode, Sian Henson discusses the characterization of a subset of human effector memory CD8+ T cells that reexpress the naïve T cell marker CD45RA (EMRA cells). Despite their senescent-like state, EMRA cells exhibited potent cytotoxic activity, the energy for which was generated by anaerobic glycolysis. Inhibition of p38 MAPK signaling in EMSA cells reversed senescent phenotypes and increased autophagy. These results indicate that some aspects of CD8+ T cell senescence may be reversible.
β cell dysfunction is a hallmark of type 2 diabetes (T2D) and is associated with extracellular accumulation of amyloid plaques comprised of islet amyloid polypeptide (IAPP). Human IAPP is potentially toxic and has been shown to accumulate within β cells of T2D patients and in transgenic rodent models. In this episode, Safia Costes and colleagues examine the role of autophagy in the degradation of human IAPP in murine models. Human IAPP aggregated within p62-positive inclusions in transgenic animals, with no apparent loss of β cell function or mass; however, human IAPP-expressing mice with a β cell-specific autophagy defect developed overt diabetes due β cell death. These results indicate that autophagy is protective against IAPP-induced toxicity in β cells and suggest the autophagy pathway as a potential theraputic target for treatment and/or prevention of T2D.
Copyright © 2014 American Society for Clinical Investigation