Journal of Clinical Investigation online early table of contents: June 5, 2008

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Public release date: 5-Jun-2008

http://www.eurekalert.org/pub_releases/2008-06/joci-joe060208.php

Contact: Honey

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Journal of Clinical Investigation

JCI online early table of contents: June 5, 2008

EDITOR'S PICK: Finding the source: cells that initiate a common infant

tumor identified

Infantile hemangiomas, exemplified by the strawberry-like patches that

appear on the skin of infants soon after birth, are benign tumors that

develop in 5%-10% of Caucasian infants and usually disappear by the age

of 9 without treatment. Joyce Bischoff and colleagues, at Children's

Hospital Boston, have now identified the cells that give rise to these

tumors and used them to develop a new mouse model of this disease.

Cells expressing the protein CD133 were isolated from infantile

hemangioma tissue and individual cells were grown separately in culture.

After each cell had been grown long enough for it to have given rise to

a large population of cells, the cells were transplanted into

immunodeficient mice, where they generated human blood vessels.

Overtime, the number of blood vessels decreased and fat cells became

evident. As these observations recapitulate those made in individuals

with infantile hemangioma — where blood vessels form and then disappear

leaving behind fat cells — the authors conclude that a single cell can

give rise to infantile hemangioma and that their new model of these

tumors will help identify therapeutic targets.

TITLE: Multipotential stem cells recapitulate human infantile hemangioma

in immunodeficient mice

AUTHOR CONTACT:

Joyce Bischoff

Children's Hospital Boston, Harvard Medical School, Boston,

Massachusetts, USA.

Phone: ; Fax: ; E-mail:

joyce.bischoff@....

View the PDF of this article at:

https://www.the-jci.org/article.php?id=33493

GASTROENTEROLOGY: The protein IRF4 takes control of inflammation in the gut

Individuals with inflammatory bowel diseases (IBDs) experience episodes

of inflammation in their gut that can cause abdominal pain, vomiting,

and diarrhea, among other things. Exactly what causes IBD has not been

determined but it is now considered to involve inappropriate over

activation of the immune system in the gut, and the proinflammatory

factor IL-6 is thought to have a crucial role in this. New insight into

the molecular mechanisms controlling IL-6 production in a mouse model of

IBDs has now been provided by Markus Neurath and colleagues, at the

University of Mainz, Germany, and might lead to the development of new

drugs to treat individuals with IBDs.

Initial analysis indicated that a molecule known as IRF4, which

regulates several functions in immune cells known as T cells, was

expressed at higher levels in T cells in the gut of individuals with

IBDs than in the gut of healthy individuals. Consistent with increased

IRF4 having an important role in the development of IBD, T cells from

mice lacking IRF4 did not cause intestinal inflammation when

transplanted into immunodeficient mice, whereas normal T cells did.

Further, IRF4-deficient mice were protected from intestinal inflammation

in two other models of IBD, and this protection was overcome by the

administration of IL-6 to the mice. The authors therefore conclude that

IRF4 is a crucial regulator of IL-6 production in the intestine and that

targeting IRF4 might provide a new approach to treating individuals with

IBDs.

TITLE: The transcription factor IFN regulatory factor-4 controls

experimental colitis in mice via T cell–derived IL-6

AUTHOR CONTACT:

Markus F. Neurath

University of Mainz, Mainz, Germany.

Phone: 49-6131-175740; Fax: 49-6131-175583; E-mail:

neurath@....

View the PDF of this article at:

https://www.the-jci.org/article.php?id=33227

NEUROBIOLOGY: Improving brain function in rats following a stroke

A team of researchers from Academia Sinica, Taipei, Republic of China,

and China Medical University Hospital, Taichung, Republic of China, have

now shown that rats transplanted with cells isolated from human nasal

polyps have improved brain function following a stroke compared with

rats not transplanted with these cells. The authors therefore suggest

that isolating these cells from individuals who have had a stroke and

transplanting them back into the brains of these individuals might

provide clinical benefit.

In the study, cells known as olfactory ensheathing cells (OECs) and

olfactory nerve fibroblasts (ONFs) were isolated from human nasal polyps

and characterized in vitro. Rats implanted with human OECs and ONFs

performed better in tasks measuring their brain function (e.g., tasks

assessing their movement) following a stroke than did rats not

transplanted with these cells. Further work determined some of the

mechanisms by which OECs and ONFs mediated their beneficial effects.

Specifically, OECs and ONFs induced nerve cell growth by a process that

involved increased expression of the soluble factor SDF-1-alpha, the

protein to which it binds, and cellular prion protein. In addition, when

transplanted into mice, OECs and ONFs induced stem cells to home to the

site of brain damage following a stroke.

TITLE: Implantation of olfactory ensheathing cells promotes

neuroplasticity in murine models of stroke

AUTHOR CONTACT:

Hung Li

Institute of Molecular Biology, Academia Sinica, Taipei, Republic of China.

Phone: 886-2-2788-0460; Fax: 886-2-2782-6085; E-mail:

hungli@....

Demeral Liu

China Medical University Hospital, Taichung, Republic of China.

Phone: 886-4-22052121 ext. 6034; Fax: 886-4-22080666; E-mail:

liudm@....

View the PDF of this article at:

https://www.the-jci.org/article.php?id=34363

NEPHROLOGY: New molecular link between diabetes and kidney failure

Diabetes is an increasingly common cause of kidney failure in developed

countries. It is thought that activation of a hormone system known as

the renin-angiotensin system (RAS) early in the course of diabetes has

an important role in the development of kidney disease. New data,

generated using mice, rats, and rabbits, by János Peti-di and

colleagues, at the University of Southern California, Los Angeles, have

provided new insight into the mechanisms by which the RAS might be

activated in individuals with diabetes.

Individuals with diabetes have increased levels of glucose in their

blood and other bodily fluids. In the study, in vitro exposure of rat,

mouse, and rabbit kidney to high levels of glucose triggered cells in

the kidney to release renin and this was associated with accumulation of

a molecule known as succinate. Consistent with this having a role in

human diabetes, diabetic mice had higher levels of succinate in their

kidney than did nondiabetic mice. Furthermore, diabetic mice lacking the

protein GPR91, which recognizes succinate, had less renin in their

kidney that did diabetic mice expressing GPR91. The authors therefore

suggest that GPR91 might be a new therapeutic target to prevent the

kidney failure that can be a complication of diabetes.

TITLE: Succinate receptor GPR91 provides a direct link between high

glucose levels and renin release in murine and rabbit kidney

AUTHOR CONTACT:

János Peti-di

University of Southern California, Los Angeles, California, USA.

Phone: ; Fax: ; E-mail: petopete@....

View the PDF of this article at:

https://www.the-jci.org/article.php?id=33293

INFLAMMATION: Why alcohol is bad for your pancreas

Much is known about the mechanisms by which excessive alcohol

consumption causes damage to organs such as the liver, heart, and brain.

However, only recently has progress been made in understanding how

excessive alcohol consumption causes damage to the pancreas, and new

insight into the molecular mechanisms underlying pancreatic damage in

mice following alcohol exposure has now been provided by Herbert Gaisano

and colleagues at the University of Toronto and University Health

Network, Canada.

Rodents who have been fed alcohol in their diet and then exposed to a

drug known as carbachol develop an inflammation of the pancreas

(pancreatitis) that resembles the pancreatitis seen in individuals who

consume an excessive amount of alcohol. It has been suggested previously

that the rodents develop pancreatitis because the alcohol and carbachol

exposure cause cells in the pancreas to release vesicles containing

degradative proteins known as enzymes at inappropriate places. In the

study, a protein known as VAMP8 was found to have an important role in

coordinating the inappropriate release of enzyme-containing vesicles in

mice exposed to alcohol and carbachol. As such, mice lacking VAMP8

showed reduced pancreatitis after exposure to alcohol and carbachol.

TITLE: VAMP8 is the v-SNARE that mediates basolateral exocytosis in a

mouse model of alcoholic pancreatitis

AUTHOR CONTACT:

Herbert Y. Gaisano

University of Toronto, Toronto, Ontario, Canada.

Phone: ; Fax: ; E-mail:

herbert.gaisano@....

View the PDF of this article at:

https://www.the-jci.org/article.php?id=34672

PHYSIOLOGY: The protein Hip1r soothes the stomach

New data, generated in mice, by son and colleagues, at the

University of Michigan, Ann Arbor, have defined a new role for the

protein Hip1r in ensuring that cells in the lining of the stomach that

are known as parietal cells function normally.

One of the main functions of parietal cells is to secrete acid, which is

stored inside special compartments in the cell known as vesicles, into

the stomach to promote the digestion of food. As Hip1r was found to be

required for parietal cells to transport their acid-containing vesicles

to the surface where the acid is released, mice lacking Hip1r had less

acid in their stomach. In addition, the defect in acid-containing

vesicle transport caused many of the parietal cells to die by a process

known as apoptosis. These effects were associated with other changes in

the lining of the stomach that resembled changes seen in the human

stomach lining in the progression to stomach cancer. The authors

therefore conclude that Hip1r has an important role in maintaining

normal stomach function.

TITLE: Hip1r is expressed in gastric parietal cells and is required for

tubulovesicle formation and cell survival in mice

AUTHOR CONTACT:

C. son

The University of Michigan, Ann Arbor, Michigan, USA.

Phone: ; Fax: ; E-mail: lcsam@....

View the PDF of this article at:

https://www.the-jci.org/article.php?id=33569

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