News Release

JCI table of contents, 15 October, 2003

Peer-Reviewed Publication

JCI Journals

FGF-2 to the rescue following traumatic brain injury

In the October 15 issue of the Journal of Clinical Investigation, Michael Moskowitz and colleagues from Harvard Medical School report that fibroblast growth factor-2 (FGF-2) plays a critical role in the ability of the brain to make new cells following traumatic brain injury (TBI). The authors also demonstrate that administration of FGF-2 boosts the production of new brain cells and protects existing neurons from degeneration following injury. The study suggests that FGF-2 supplementation may improve the outcome of individuals who suffer TBI following motor vehicle accidents or other brain injuries.

The brain can be distinguished from other organs and tissues of the body by its limited ability to repair itself. This lack of self-repair following TBI or disease can often result in severe deficits in cognitive, physical, and psychological skills.

However, in the last several decades, mounting evidence has led to the view of the brain as a dynamic, plastic organ, endowed with some potential for self-repair and regeneration. Recent progress in understanding continued neurogenesis – the generation of new neurons (nerve cells) -– in the adult brain has raised hopes that self-renewal leading to structural repair by new neurons may even be possible.

Moskowitz and fellow researchers examined the role of FGF-2 in the regulation of neurogenesis and neuron loss in a specific region of the brain known as the hippocampal dentate gyrus (DG), in an animal model of TBI. Mice lacking FGF-2, showed a decreased ability to protect existing neurons and generate new neurons following TBI, when compared to controls, indicating that FGF-2 plays a critical role in stabilizing cell loss following injury.

In an effort to limit cell loss and enhance cell proliferation in the DG following TBI, the authors administered FGF-2 by gene delivery and found that this method was indeed able to limit the loss of existing neurons while simultaneously increasing the proliferation of new neurons in this region of the brain.

The data suggest that FGF-2 supplementation might provide a rational strategy to treat brain injury by simultaneously enhancing neurogenesis and reducing neurodegeneration.

In an accompanying Spotlight article on neurogenesis and brain injury, Daniel A. Peterson and colleagues from Chicago Medical School discuss the most recent developments in managing renewable cells for post-injury brain repair.

TITLE: FGF-2 regulates neurogenesis and degeneration in the dentate gyrus after traumatic brain injury in mice

AUTHOR CONTACT:
Michael A. Moskowitz
Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Phone: (617) 726-8442
Fax: (617) 726-2547
E-mail: Moskowitz@helix.mgh.harvard.edu

View the PDF of this article at: https://www.the-jci.org/press/16618.pdf

ACCOMPANYING SPOTLIGHT:
Neurogenesis and brain injury: managing a renewable resource for repair

AUTHOR CONTACT:
Daniel A. Peterson
Department of Neuroscience, The Chicago Medical School, North Chicago, Illinois, USA.
Phone: (847) 578-3411
Fax: (847) 578-8545
E-mail: daniel.peterson@finchcms.edu

View the PDF of this Spotlight article at: https://www.the-jci.org/press/20098.pdf


Enigmatic role for NF-kappaB in the hardening of arteries

A report in the October 15 issue of the Journal of Clinical Investigation resulting from a collaboration led by Menno P.J. de Winther and researchers at Vrije University, Maastricht University, Technical University of Munich, and Harvard Medical School, reveals that inhibition of the transcription factor NF-kappaB increases atherosclerosis – a chronic inflammatory disease that causes the progressive narrowing and hardening of arteries over time.

An initiating event in the development of atherosclerosis is the accumulation within vessels of lipids such as low-density lipoprotein (LDL), which acts as a carrier for cholesterol and fats in the bloodstream. Modification of these lipids induces inflammatory processes, which recruit macrophages from the blood that consume LDL, thereby creating lesions that ultimately cause vessel narrowing and restriction of blood flow.

The role of NF-kappaB in atherosclerosis has been controversial. NF-kappaB is known to induce expression of inflammatory genes that play detrimental roles in atherosclerosis. On the other hand, NF-kappaB is also a survival factor and may promote expression of certain anti-inflammatory agents.

To investigate the role of NF-kappaB activation in macrophages during atherogenesis, de Winter and colleagues studied mice deficient in the LDL receptor and the enzyme IkappaB kinase 2, which is essential for NF-kappaB activation. The authors showed that NF-kappaB –defective macrophages enhance, rather than inhibit, atherosclerosis. Lesions were larger in size, more advanced, and contained more necrosis, and early lesions contained more macrophages.

The authors suggest that inhibition of the NF-kappaB pathway may increase the severity of atherosclerosis by affecting the delicate balance between the expression of pro- and anti-inflammatory factors.

TITLE: Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor–deficient mice

AUTHOR CONTACT:
Menno P. J. de Winther
Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
Phone: +31-43-3881897
Fax: +31-43-3884574
E-mail: dewinther@gen.unimaas.nl

View the PDF of this article at: https://www.the-jci.org/press/18580.pdf


Researchers closer to understanding tuberous sclerosis

David Kwiatkowski and fellow researchers at Harvard Medical School have new evidence that may help explain how two genes that are mutated in patients with tuberous sclerosis complex (TSC), a genetic disorder that produces widespread benign tumors in the brain, skin, lungs, and kidneys, contribute to regulating cell growth and organ size.

TSC is caused by mutations in either of two classic tumor suppressor genes, TSC1 and TSC2, both of which interact with the insulin receptor PI3K-Akt-S6k- and mTOR signaling pathways that are known to be widely involved in human cancer. In this report, the authors demonstrate that TSC2-/- mouse embryo fibroblasts display dysregulated levels of phosphorylation of key components of these pathways, which may account for the lack of Akt activation in TSC2-/- cells. The report confirms and extends the current model of TSC2 function in cell growth regulation. The study may also explain why the progression of TSC-associated tumors to malignancy is rare.

TITLE: Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR

AUTHOR CONTACT:
David J. Kwiatkowski
Genetics Laboratory, Boston, Massachusetts, USA.
Phone: (617) 278-0384
Fax: (617) 734-2248
Email: dk@rics.bwh.harvard.edu

View the PDF of this article at: https://www.the-jci.org/press/17222.pdf


Infection gives Toll-like receptors something to talk about

The lining of blood vessels, known as the vascular endothelium, comprises multifunctional cells that play important roles in maintaining blood pressure, clotting, the immune response, and inflammation. Following injury or infection, vascular endothelial cells regulate the migration of polymorphonuclear neutrophils (PMNs) to the site of injury. Toll-like receptor (TLR) -2 and TLR4, are expressed by many first-line host defense molecules, including PMNs, and act to recognize pathogens and initiate the immune response. Asrar Malik and colleagues from the University of Illinois School of Medicine demonstrate that during infection, the activation of PMNs via TLR4 instructs endothelial cells to upregulate TLR2 and therefore further sensitizes these cells to foreign invaders and drives the immune response in a positive feedback loop. The authors report that this "message" is sent by the release of free oxygen radicals following cell-cell interaction. This communication between receptors is called "cross talk".

In an accompanying commentary, Eicke Latz and Douglas Golenbock from the University of Massachusetts Medical School comment, "this complex process of temporally regulated reponses to microbes via different TLRs is unlikely to be restricted to bacteria. Recent studies, for example, have documented the recognition of herpes viruses by TLR2. The general theme is that, as pathogens march through their target cells, a highly coordinated and intricate immune response program is likely initiated".

The report indicates the important role of TLR4 signaling and subsequent TLR2 activation in amplifying the migration of PMNs to the sites of infection.

TITLE: TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase

AUTHOR CONTACT:
Asrar B. Malik
University of Illinois College of Medicine, Chicago, Illinois, USA.
Phone: (312) 996-7635
Fax: (312) 996-1225
E-mail: abmalik@uic.edu

View the PDF of this article at: https://www.the-jci.org/press/18696.pdf

ACCOMPANYING COMMENTARY:
Receptor "cross talk" in innate immunity

AUTHOR CONTACT:
Douglas T. Golenbock
University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Phone: (508) 856 -5982
Fax: (508) 864 -5463
E-mail: douglas.golenbock@umassmed.edu

View the PDF of this commentary at: https://www.the-jci.org/press/20040.pdf


Attracting pericytes to tumor blood vessels: it's all in the presentation

The supply of blood to a tumor requires new blood vessel formation (vasculogenesis) and the sprouting and bridging of existing blood vessels (angiogenesis). Endothelial cells (ECs) line blood vessels and attract mural cells, including pericytes, to the vessel wall. Vessels without pericytes demonstrate abnormal branching patterns and leakiness. Because of their critical role in tumor growth, tumor blood vessels are recognized as potential antitumor drug targets. Previous studies have demonstrated that pericyte recruitment to blood vessels during normal angiogenesis depends on interaction between the growth factor PDGF-B, expressed by ECs, and PDGF-Rbeta, expressed by pericytes. It has however been unclear if these factors are similarly involved in pathological angiogenesis during tumor formation and, if so, the precise mechanism underlying pericyte recruitment.

Christer Betsholtz and colleagues at the Sahlgrenska Academy at Göteborg University, Sweden, propose that it is not just the presence of PDGF-B, but how it is presented by ECs to pericytes that determines the quality of vessel development. The authors provide evidence to suggest that an increased amount of PDFG-B is located adjacent to ECs, which coaxes pericytes into close contact. The presence of a characteristic "retention motif", a region that helps PDGF-B bind to the cell surface is also suggested to help PDGF-B localize in or near ECs. Betsholtz and colleagues found that without this motif pericyte recruitment was limited, and existing pericytes were partially detached from the vessel wall, which resulted in hemorrhaging. The report supports the notion that pericytes serve an important function in tumor vessels and highlights PDGF-B and PDGF-Rbeta as promising targets for therapeutic intervention in the treatment of tumors.

TITLE: Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors

AUTHOR CONTACT:
Christer Betsholtz
Göteborg University, Göteborg, Sweden.
Phone: +46-31-7733460
Fax: +46-31-4161108
E-mail: Christer.Betsholtz@medkem.gu.se

View the PDF of this article at: https://www.the-jci.org/press/18549.pdf

ACCOMPANYING COMMENTARY:
What brings pericytes to tumor vessels?

AUTHOR CONTACT:
Rakesh K. Jain
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 726-4083
Fax: (617) 724-1819
E-mail: jain@steele.mgh.harvard.edu

View the PDF of this commentary at: https://www.the-jci.org/press/20087.pdf


Researchers identify a small gene deletion associated with pseudohypoparathyroidism-Ib

Parathyroid hormone (PTH) is produced by the parathyroid gland and helps regulate calcium and phosphate levels in the blood. The condition, pseudohypoparathyroidism (PHP) is a genetic disorder where there is an adequate level of PTH however the body cannot respond to it. PHP type Ib (PHP-Ib) is characterized by resistance to PTH confined to the kidney, which causes dysregulation of calcium and phosphate levels. Harald Jüppner and colleagues from Massachusetts General Hospital, Boston, have previously shown that PHP-Ib is genetically linked to a region on chromosome 20q13.3 that includes the gene GNAS. All previous studies of PHP-Ib cases have described a loss of methylation at the maternal GNAS exon A/B, suggesting that PHP-Ib is caused by a mutation or mutations in an element of GNAS that controls exon A/B methylation. Through further genetic analysis of a number of unrelated affected individuals and gene carriers, Jüppner and colleagues have now identified a small microdeletion upstream of GNAS exon A/B that results in a loss of exon A/B methylation and propose that it is this genetic defect that underlies renal PTH resistance in PHP-Ib.

TITLE: Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS

AUTHOR CONTACT:
Harald Jüppner
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: (617) 726-3966
Fax: (617) 726-7543
E-mail: jueppner@helix.mgh.harvard.edu

View the PDF of this article at: https://www.the-jci.org/press/19159.pdf


T cell activation throws lupus for a loop

Lupus is an autoimmune disease where an individual produces antibodies against their own body tissues. In a mouse model of lupus, treatment with alpha-galactosylceramide (alphaGalCer), a ligand of natural killer T cells, has been shown to ameliorate disease by changing the immune response from pathogenic (Th1-type) to nonpathogenic (Th2-type). In contrast, Defu Zheng and colleagues from Stanford University School of Medicine and the La Jolla Institute of Allergy and Immunology in California found that in an alternative mouse model of lupus, treatment with alphaGalCer caused an abnormal Th1-type immune response that in fact exacerbated disease. Treatment with blocking anti-Cd1d monoclonal antibodies augmented the immune response and ameliorated disease. In their report, the authors suggest reasons for the observation that activation of natural killer T cells contributes to lupus development and suggest that anti-CD1d monoclonal antibodies might be useful in the treatment of lupus.

TITLE: Activation of natural killer T cells in NZB/W mice induces Th1-type immune responses exacerbating lupus

AUTHOR CONTACT:
Defu Zeng
The Beckman Research Institute, Duarte, California, USA.
Phone: (626) 359-8111 ext. 62587
Fax: (626) 301-8136
E-mail: dzeng@coh.org

View the PDF of this article at: https://www.the-jci.org/press/17165.pdf


A novel role for uroguanylin in the regulation of sodium balance

Uroguanylin is a peptide hormone that regulates sodium excretion by the kidney when excess salt is consumed. A new study by John Lorenze and colleagues from the University of Cincinnati School of Medicine demonstrates that mice deficient in uroguanylin have a blunted ability to excrete sodium in their urine in response to excess oral sodium intake, and they also exhibit elevate blood pressure. The study indicates that there is a role for uroguanylin and a link between the intestine and kidney in maintaining a balance of sodium in the body.

In an accompanying commentary, Leonard Forte from the University of Missouri comments "It is clear that the seminal findings of Lorenz et al using the uroguanylin gene knockout mouse will be of major significance to investigators who are working to gain a better understanding of the regulatory mechanisms that govern body sodium balance and blood pressure".

The regulation of sodium balance is believed to be a crucial mechanism that permits the excretion of water and electrolytes from the kidney into the urine to be finely balanced with dietary salt intake.

TITLE: Uroguanylin knockout mice have increased blood pressure and impaired natriuretic response to enteral NaCl load

AUTHOR CONTACT:
John N. Lorenz
University of Cincinnati School of Medicine, Cincinnati, Ohio, USA.
Phone: (513) 558-3097
Fax: (513) 558-5738
Email: john.lorenz@uc.edu

View the PDF of this article at: https://www.the-jci.org/press/18743.pdf

ACCOMPANYING COMMENTARY:
A novel role for uroguanylin in the regulation of sodium balance

AUTHOR CONTACT:
Leonard R. Forte
University of Missouri, Columbia, Missouri, USA.
Phone: (573) 814-6000
Fax: (573) 814-6551
E-mail: lrf@missouri.edu

View the PDF of this commentary at: https://www.the-jci.org/press/20057.pdf


Immunological tug of war between IL-12 and IL-23

Experimental autoimmune encephalomyelitis (EAE) is an animal model of human multiple sclerosis. Microglia and macrophages that reside within the central nervous system (CNS) are a source of the inflammatory cytokines IL-23 and IL-12. Until recently it was considered that IL-12 was a major mediator in the development of EAE, however within the last year it has been reported that IL-23 and not IL-12 is essential in the development of EAE. Burkhard Becher and colleagues from the University of Zurich, Switzerland, and Dartmouth College, New Hampshire, USA, now show that the p40 subunit, shared by both IL-12 and IL-23, plays a critical role in maintaining encephalitogenicity during the course of this disease. The authors demonstrated that in the absence of p40 expression within the CNS, EAE was delayed and less severe. This study suggests that cells resident in the CNS can control the degree of T cell encephalitogenicity and that therapeutic intervention by targeting the IL-12/23 pathway may provide a powerful inhibitor of multiple sclerosis disease progression without the side-effects of broad immune suppression.

TITLE: IL-23 produced by CNS-resident cells controls T cell encephalitogenicity during the effector phase of experimental autoimmune encephalomyelitis

AUTHOR CONTACT:
Burkhard Becher
University Hospital of Zurich, Zurich, Switzerland.
Phone: +41-0-1-255-8842
Fax: +41-0-1-255-9765
Email: burkhard.becher@usz.ch

View the PDF of this article at: https://www.the-jci.org/press/19079.pdf


Long-lost ancestral liver cells are found

The liver is the central organ of nutrient digestion and metabolism. In adult life, it is a quiescent organ, except when subjected to injury, when it responds with neoproliferation of mature hepatocytes and other liver cells to the point of complete organ regeneration. There is also a contribution from resident hepatic stem cells, about which little is known. Miguel Marcos and colleagues from Universidad Autónoma de Madrid, Spain, now describe a population of embryonic ancestor cells, called progenitors, in the liver that selectively express liver-specific genes and proteins during development. These cells were evaluated for their growth potential, differentiation, and clonal growth in media supplemented with different growth factors. The authors demonstrated that purified progenitor cells cocultured with cell-depleted fetal liver fragments successfully engrafted and repopulated liver compartments, suggesting that they may be the embryonic stem cells responsible for liver development.

TITLE: A population of c-Kitlow(CD45/TER119)– hepatic cell progenitors of 11-day postcoitus mouse embryo liver reconstitutes cell-depleted liver organoids

AUTHOR CONTACT:
Miguel A.R. Marcos
Centro de Biología Molecular Severo Ochoa, Madrid, Spain.
Phone: +34-91-397-8053
Fax: +34-91-397-8087
E-mail: marmarcos@cbm.uam.es

View the PDF of this article at: https://www.the-jci.org/press/17409.pdf


HESX1 puts a hex on the pituitary gland

The gene HESX1 encodes a developmental repressor and is expressed in early development in the forebrain and later in the anterior pituitary gland. Mutations within HESX1 are associated with septo-optic dysplasia and mild hypopituitarism. Mehul Dattani and colleagues from the London Centre for Paediatric Endocrinology now describe the clinical characteristics and functional consequence of only the second homozygous mutation within HESX1. The authors identify a missense mutation in the critical Engrailed homology repressor domain of HESX1 that normally mediates recruitment of Groucho homolog/Transducin-like enhancer of split-1 (TLE1). The authors present functional analyses demonstrating the mutation-induced disruption of HESX1/TLE1 interaction and transcriptional repression in cultured cells. These results provide a striking example of a clinical disorder associated with the loss of repressor/corepressor interactions. Further study of HESX1 mutations should reveal crucial insights into the functional role of this gene in human embryogenesis.

TITLE: A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction

AUTHOR CONTACT:
Mehul T. Dattani
London Centre for Paediatric Endocrinology, Great Ormond Street Children's Hospital, London, United Kingdom
Phone: +44-20-7905-2657
Fax: +44-20-7404-6191
Email: mdattani@ich.ucl.ac.uk

View the PDF of this article at: https://www.the-jci.org/press/18589.pdf


Antibodies fend off fungal respiratory infection

Histoplasma capsulatum is the most common cause of fungal respiratory infections in the world and poses a particular threat to the elderly and immunocompromised patients such as those with HIV or organ transplant recipients undergoing immunosuppressive drug therapy. Using a mouse model of histoplasmosis, Joshua Nosanchuk and colleagues from Albert Einstein College of Medicine in New York have identified monoclonal antibodies that targeted the histone H2B-like protein of H. capsulatum and reduced fungal burden, diminished inflammation, and prolonged host survival. While vaccine development for H. capsulatum is an exciting area of research, vaccination may not be effective in immunocompromised individuals. Therefore it is conceivable that this group of individuals may benefit from passive therapy with specific monoclonal antibodies to H. capsulatum, such as those described in this report.

TITLE: Antibodies to a cell surface histone-like protein protect against Histoplasma capsulatum

AUTHOR CONTACT:
Joshua D. Nosanchuk
Albert Einstein College of Medicine, New York, New York, USA.
Phone: (718) 430-3766
Fax 1: (718) 430-8701
E-mail: nosanchu@aecom.yu.edu

View the PDF of this article at: https://www.the-jci.org/press/19361.pdf


###


Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.