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JCI online early table of contents: June 13, 2011

EDITOR'S PICK: Sniffing out a new source of stem cells

A team of researchers, led by Emmanuel Nivet, now at the Salk Institute for Biological Studies, La Jolla, has generated data in mice that suggest that adult stem cells from immune system tissue in the smell-sensing region of the human nose (human olfactory ectomesenchymal stem cells [OE-MSCs]) could provide a source of cells to treat brain disorders in which nerve cells are lost or irreparably damaged.

Stem cells are considered by many to be promising candidate sources of cells for the regeneration and repair of tissues damaged by various brain disorders (including traumatic brain injury). There are two types of stem cell usually considered in this therapeutic context: embryonic stem (ES) cells, which are derived from early embryos; and induced pluripotent stem (iPS) cells, which are derived by reprogramming cells of the body such that they have the ability to generate any cell type. Ethical and technical issues have so far limited clinical development of therapeutic approaches using ES and iPS cells, respectively, meaning that researchers are seeking alternative stem cell sources. Nivet and colleagues found that upon transplantation into mice with damage to the hippocampal region of their brain (a region important for learning and memory) OE-MSCs moved toward the site of damage, where they developed into nerve cells and also stimulated endogenous nerve cell generation. Importantly, the treated mice showed improvement in learning and memory. These data suggest OE-MSCs might be of tremendous utility in the clinic.

TITLE: Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions

Emmanuel Nivet
Salk Institute for Biological Studies, La Jolla, California, USA.
Phone: 858.453.4100, ext. 1324; Fax: 858.453.2573; E-mail:

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ONCOLOGY: Small but powerful cancer probe

Nanoparticle-based materials are under development for many clinical uses; for example, they are being developed for use as drug-delivery vehicles and diagnostic probes. However, many such materials currently under evaluation in oncology clinical trials are not tumor selective. Now, a team of researchers, led by Michelle Bradbury, at the Sloan-Kettering Institute for Cancer Research, New York, has characterized an approximately 7-nm diameter multimodal silica nanoparticle that is tumor selective and nontoxic. Importantly, the team used these particles to image tumor spread in a spontaneous skin cancer miniswine model. The authors therefore suggest that their data highlight the potential of these cancer-selective silica nanoparticles for determining disease spread in the clinical setting, something that could become a reality sooner rather than later because the nanoparticles were recently approved for a first-in-human clinical trial.

TITLE: Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma

Michelle S. Bradbury
Sloan-Kettering Institute for Cancer Research, New York, New York, USA.
Phone: 212.639.8938; Fax: 212.794.4010; E-mail:

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PULMONARY: New way to treat pulmonary hypertension?

Pulmonary arterial hypertension (PAH) is a severe disease of the arterial blood vessels in the lungs that leads to progressive failure of the right side of the heart and premature death. There is no cure for PAH. However, recent advances in understanding the mechanisms underlying PAH have led to new, clinically beneficial therapeutic approaches. A team of researchers, led by Jean-Sbastien Hulot, at Universit Pierre et Marie Curie, France, has gained new insight into the mechanisms underlying PAH that leads them to suggest that inhibiting the protein MRP4 could provide a new way to treat individuals with PAH.

The initial analysis of Hulot and colleagues indicated that expression of MRP4 was markedly higher in lung samples from patients with clinical pulmonary hypertension than in those from healthy individuals. Consistent with a role for MRP4 in the development of PAH, mice lacking MRP4 were protected from pulmonary hypertension. Of clinical importance, treatment of normal mice with an inhibitor of MRP4 reversed pulmonary hypertension. These data provide the rationale for the authors' suggestion that MRP4 could be targeted for the treatment of PAH.

TITLE: Inhibition of MRP4 prevents and reverses pulmonary hypertension in mice

Jean-Sbastien Hulot
Universit Pierre et Marie Curie, INSERM UMR956, Paris, France.
Phone:; Fax:; E-mail:

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AGING: Growing old gracefully: premature aging condition provides clues about normal aging

A team of researchers, led by Francis Collins, at the National Institutes of Health, Bethesda, has now linked a mutant protein that is key to a devastating premature aging disease to the normal aging process.

Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disease that dramatically accelerates the aging process; children with HGPS die at an average age of 12 years. It is caused by mutations in the LMNA gene that lead to the production of a mutant protein known as progerin. Recently, progerin was found at low levels in normal human cells and tissues, but whether it has a role in normal aging has not been determined. Collins and colleagues have now found that progerin production is triggered in normal human cells undergoing senescence the process by which normal cells lose their capacity to divide and by which they have their lifespan limited. Importantly, progerin production was only triggered during cellular senescence induced by shortening of telomeres the specialized structures at the ends of chromosomes, gradual loss of which activates senescence. These data indicate that telomere dysfunction and progerin production cooperate during the induction of cell senescence, demonstrating that understanding of the premature aging processes in individuals with HGPS is likely to provide insight into the normal aging process.

TITLE: Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblast cells

Francis S. Collins
National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
Phone: 301.496.2433; Fax: 301.402.2700; E-mail:

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INFLAMMATION: To be M1 or to be M2: the protein KLF4 decides for macrophages

Macrophages are cells critical for both immune defense against invading microbes and inflammation. They are currently classified as either M1 or M2, with M1 macrophages being considered pro-inflammatory and M2 macrophages anti-inflammatory. A team of researchers, led by Mukesh Jain, at Case Western Reserve University, Cleveland, has now identified KLF4 as a gene regulatory factor that controls macrophage polarization, a finding with broad clinical implications because levels of KLF4 can be modulated by several drugs in clinical use (e.g., statins) and dietary components (e.g., broccoli).

Jain and colleagues found that KLF4 promotes the emergence of M2 characteristics and inhibits the emergence of M1 characteristics in both human and mouse macrophages. Importantly, mice lacking KLF4 in macrophages were predisposed to developing diet-induced obesity, glucose intolerance, and resistance to the effects of the hormone insulin (all factors that lead to the development of type 2 diabetes, a disease associated with inflammation). Furthermore, expression of KLF4 was markedly less in fat tissue from obese individuals than that from lean individuals. The team therefore suggests that modulating KLF4 levels might provide a therapeutic approach for a broad spectrum of medical conditions linked to inflammation, including type 2 diabetes.

TITLE: Krppel-like factor 4 regulates macrophage polarization

Mukesh K. Jain
Case Western Reserve University, Cleveland, Ohio, USA.
Phone: 216.368.3607; Fax: 216.368.0556; E-mail:

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IMMUNOLOGY: Immune cells Vent(X) their feelings

Macrophages are cells of the immune system that play critical roles in defense against invading microbes and inflammation. While many of the signals that trigger the generation of tissue macrophages from blood cells known as monocytes have been determined, the gene regulatory mechanisms that these signals activate have not been. However, a team of researchers, led by Zhenglun Zhu, at Brigham and Women's Hospital, Harvard Medical School, Boston, has now identified VentX as a gene regulatory protein that is key to the generation of human macrophages from monocytes. Importantly, the team also found that VentX is pivotal to the proinflammatory function of human macrophages. As expression of VentX was found to correlate with expression of proinflammatory mediators in immune cells isolated from the blood of patients with autoimmune diseases, the authors suggest that dysregulation of VentX may play a role in the development of autoimmune diseases.

TITLE: The homeobox transcription factor VentX controls human macrophage terminal differentiation and proinflammatory activation

Zhenglun Zhu
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.732.5467; Fax: 617.730.5807; E-mail:

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CARDIOVASCULAR DISEASE: Fat accumulation in the heart impairs survival

The leading cause of death in the United States is a condition known as coronary heart disease, one complication of which is heart attack. Coronary heart disease is the term given to narrowing of the small blood vessels that supply blood and oxygen to the heart. As a result of the condition, there is inadequate oxygenation of the heart muscle and this promotes the accumulation of fats known as triglycerides in heart muscle cells. The accumulation of triglycerides in heart muscle cells is associated with impaired heart function, but whether the former causes the latter has not been determined. Now, a team of researchers, led by Jan Born, at Sahlgrenska University Hospital, Sweden, has found that the former does indeed cause the latter.

The team found that the protein VLDLR is required for the accumulation of triglycerides in mouse heart muscle cells under conditions of limited oxygen availability. Further, mice lacking VLDLR show improved survival and decreased damage to the heart following an induced heart attack. Importantly, VLDLR gene expression was found to be higher in human hearts deprived of full oxygenation compared with normal human hearts and correlated with fat accumulation. The team therefore suggests that VLDLR could provide a new target for the development of therapeutics for use in the early stages of a heart attack.

TITLE: The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction

Jan Born
Sahlgrenska University Hospital, Gteborg, Sweden.
Phone: 46.31.342.2949; Fax: 46.31.823.762; E-mail:

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CARDIOLOGY: The protein PDE4B helps coordinate heart muscle cell contraction

Coordinated contraction of heart muscle cells is pivotal to maintaining a steady heart beat. A team of researchers, led by Rodolphe Fischmeister and Grgoire Vandecasteele, at INSERM UMR-S 769, Universit Paris-Sud, France, has now generated new insight into the molecular control of heart muscle cell contraction, information that could have a bearing on the development of new therapeutics to treat arrhythmia dysregulation of the heart rate or heart rhythm, such as beating too fast, too slow, or irregularly.

One key step in the molecular pathway that controls heart muscle cell contraction is influx of calcium (Ca2+) from outside the cell via channels known as LTCCs. LTCCs are triggered to open by increases in levels of the signaling molecule cAMP within the cell. Levels of cAMP are themselves regulated by cyclic nucleotides phosphodiesterases (PDEs). In this study, Fischmeister, Vandecasteele, and colleagues have identified a role for PDE4B in limiting LTCC opening in mouse heart muscle cells and determined that this prevents arrhythmias. As decreased levels of PDE4b were recently observed in failing hearts, the authors suggest that their new data provide a mechanistic link between arrhythmias and sudden death in individuals with heart failure.

TITLE: Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ current and protects against ventricular arrhythmias in mice

Rodolphe Fischmeister
INSERM UMR-S 769, Universit Paris-Sud, Chtenay-Malabry, France.
Phone:; Fax; E-mail:

Grgoire Vandecasteele
INSERM UMR-S 769, Universit Paris-Sud, Chtenay-Malabry, France.
Phone:; Fax; E-mail:

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HEMATOLOGY: The protein P2X7 receptor triggers blood clot formation

Injury to blood vessel walls triggers the formation of a blood clot (thrombus). Clinically, many conditions are linked to unwanted thrombus formation (e.g., heart attack, DVT, and stroke) and antiblood clotting therapies (anticoagulants) are used widely. A potential new approach to anti-coagulant therapy is provided by work in mice performed by a team of researchers, led by Wolfram Ruf, at the Scripps Research Institute, La Jolla.

Thrombus formation is triggered by the protein TF, which is expressed on blood vessel walls, blood cells known as myeloid cells, and myeloid cellderived microparticles. How thrombus-promoting TF is generated in vivo, is, however, not well defined. Now, Ruf and colleagues have identified a role for the protein P2X7 receptor in generating thrombus-promoting TF. Specifically, they found that signaling triggered by P2X7 receptor binding to the molecule ATP induced mouse myeloid cells to produce TF-positive microparticles. They therefore suggest that targeting P2X7 receptor may represent a new approach to anti-coagulant therapy.

TITLE: P2X7 receptor signaling contributes to tissue factordependent thrombosis in mice

Wolfram Ruf
Scripps Research Institute, La Jolla, California, USA.
Phone: 858.784.2748; Fax: 858.784.8480; E-mail:

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HEMATOLOGY: Stopping transplanted cells from attacking

One potential cure for several blood cell conditions (including some forms of leukemia) is transplantation with blood or bone marrow from a genetically non-identical individual (a treatment known as allogeneic BMT). One of the most severe complications of allogeneic BMT is graft-versus-host-disease (GVHD), which occurs if immune cells known as T cells in the transplanted blood or bone marrow attack the transplant recipient's body. A team of researchers, led by Markus Mapara, at the University of Pittsburgh, Pittsburgh, has now provided new insight into immune cell interactions that control the development of GVHD. Specifically, Mapara and colleagues found that lack of the protein STAT1 in CD4+ T cells in donor blood reduced the incidence of GVHD in mouse models of allogeneic BMT. While further analysis defined the cellular mechanisms underlying this effect, the authors suggest that targeting STAT1 in CD4+ T cells could provide therapeutic benefit.

TITLE: Absence of Stat1 in donor CD4+ T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice

Markus Y. Mapara,
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
Phone: 412.623.1112; Fax: 412.623.1415; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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