General Atomics

About: General Atomics is a company organization based out in San Diego, California, United States. It is known for research contribution in the topics: Tokamak & Divertor. The organization has 3265 authors who have published 5171 publications receiving 136370 citations.

Production of pancreatic hormone–expressing endocrine cells from human embryonic stem cells

Abstract: Of paramount importance for the development of cell therapies to treat diabetes is the production of sufficient numbers of pancreatic endocrine cells that function similarly to primary islets We have developed a differentiation process that converts human embryonic stem (hES) cells to endocrine cells capable of synthesizing the pancreatic hormones insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, gut-tube endoderm, pancreatic endoderm and endocrine precursor--en route to cells that express endocrine hormones The hES cell-derived insulin-expressing cells have an insulin content approaching that of adult islets Similar to fetal beta-cells, they release C-peptide in response to multiple secretory stimuli, but only minimally to glucose Production of these hES cell-derived endocrine cells may represent a critical step in the development of a renewable source of cells for diabetes cell therapy

Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo

Abstract: Development of a cell therapy for diabetes would be greatly aided by a renewable supply of human β-cells. Here we show that pancreatic endoderm derived from human embryonic stem (hES) cells efficiently generates glucose-responsive endocrine cells after implantation into mice. Upon glucose stimulation of the implanted mice, human insulin and C-peptide are detected in sera at levels similar to those of mice transplanted with ~3,000 human islets. Moreover, the insulin-expressing cells generated after engraftment exhibit many properties of functional β-cells, including expression of critical β-cell transcription factors, appropriate processing of proinsulin and the presence of mature endocrine secretory granules. Finally, in a test of therapeutic potential, we demonstrate that implantation of hES cell–derived pancreatic endoderm protects against streptozotocin-induced hyperglycemia. Together, these data provide definitive evidence that hES cells are competent to generate glucose-responsive, insulin-secreting cells. Development of a cellular therapy for the amelioration of diabetes requires a renewable source of human insulin–secreting cells that respond to glucose in a physiologic manner. Currently, cellular replacement is performed either by whole-pancreas transplant or by infusion of isolated primary islets into the portal vein 1 . These procedures, although effective, are not suitable for the general diabetes population, primarily because of the inadequate supply of organs and the necessity of chronic immunosuppression. One approach to overcoming the problem of insufficient supply is to generate islets from proliferative stem cell populations. Currently, the only stem cell population with sufficient proliferative capacity to achieve this goal is human embryonic stem (hES) cells, which proliferate in culture at a rate of >250 population doublings per year 2,3 . Of equal importance, hES cells are capable of efficiently and rapidly differentiating through a series of defined developmental transitions to generate cells of all somatic lineages. This competence has allowed us to produce definitive endoderm cells 4 , foregut, pancreatic and endocrine precursor cells 5 and ultimately insulin-secreting cells 5 . However, in previous studies, functional characterization of hES cells differentiated to endocrine populations showed insulin secretion in response to various secretagogues but not to glucose in vitro 5 or in vivo 6 . Fetal human pancreatic tissues at 14–20 weeks 7–9 or 6–9 weeks 10,11 of age have been shown to develop functionally after implantation in animals. At 6–9 weeks, only a few hormone-expressing endocrine cells, which do not respond to glucose, are present in the fetal human pancreatic anlagen. After implantation, these tissues differentiate

Efficient differentiation of human embryonic stem cells to definitive endoderm.

Abstract: The potential of human embryonic stem (hES) cells to differentiate into cell types of a variety of organs has generated much excitement over the possible use of hES cells in therapeutic applications. Of great interest are organs derived from definitive endoderm, such as the pancreas. We have focused on directing hES cells to the definitive endoderm lineage as this step is a prerequisite for efficient differentiation to mature endoderm derivatives. Differentiation of hES cells in the presence of activin A and low serum produced cultures consisting of up to 80% definitive endoderm cells. This population was further enriched to near homogeneity using the cell-surface receptor CXCR4. The process of definitive endoderm formation in differentiating hES cell cultures includes an apparent epithelial-to-mesenchymal transition and a dynamic gene expression profile that are reminiscent of vertebrate gastrulation. These findings may facilitate the use of hES cells for therapeutic purposes and as in vitro models of development.

IAPs block apoptotic events induced by caspase‐8 and cytochrome c by direct inhibition of distinct caspases

Abstract: Inhibitor of apoptosis (IAP) gene products play an evolutionarily conserved role in regulating programmed cell death in diverse species ranging from insects to humans. Human XIAP, cIAP1 and cIAP2 are direct inhibitors of at least two members of the caspase family of cell death proteases: caspase-3 and caspase-7. Here we compared the mechanism by which IAPs interfere with activation of caspase-3 and other effector caspases in cytosolic extracts where caspase activation was initiated by caspase-8, a proximal protease activated by ligation of TNF-family receptors, or by cytochrome c, which is released from mitochondria into the cytosol during apoptosis. These studies demonstrate that XIAP, cIAP1 and cIAP2 can prevent the proteolytic processing of pro-caspases -3, -6 and -7 by blocking the cytochrome c-induced activation of pro-caspase-9. In contrast, these IAP family proteins did not prevent caspase-8-induced proteolytic activation of pro-caspase-3; however, they subsequently inhibited active caspase-3 directly, thus blocking downstream apoptotic events such as further activation of caspases. These findings demonstrate that IAPs can suppress different apoptotic pathways by inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis.

Fast ignition by intense laser-accelerated proton beams.

Abstract: The concept of fast ignition with inertial confinement fusion (ICF) is a way to reduce the energy required for ignition and burn and to maximize the gain produced by a single implosion. Based on recent experimental findings at the PETAWATT laser at Lawrence Livermore National Laboratory, an intense proton beam to achieve fast ignition is proposed. It is produced by direct laser acceleration and focused onto the pellet from the rear side of an irradiated target and can be integrated into a hohlraum for indirect drive ICF.