Molecule Created That Nudges Nerve Stem Cells To Mature

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Molecule Created That Nudges Nerve Stem Cells To Mature

http://medicalnewscenter.com/out/out.cgi?

http://www.sciencedaily.com/releases/2008/06/080615142250.htm

Inspired by a chance discovery during another experiment, researchers

at UT Southwestern Medical Center have created a small molecule that

stimulates nerve stem cells to begin maturing into nerve cells in

culture.

This finding might someday allow a person's own nerve stem cells to

be grown outside the body, stimulated into maturity, and then re-

implanted as working nerve cells to treat various diseases, the

researchers said.

" This provides a critical starting point for neuro-regenerative

medicine and brain cancer chemotherapy, " said Dr. Hsieh,

assistant professor of molecular biology and senior author of the

paper, which appears online June 15 and in the June 17 issue of

Nature Chemical Biology.

The creation of the molecule allowed the researchers to uncover some

of the biochemical steps that happen as nerve cells mature. It also

showed that large-scale screening of compounds can provide starting

points for developing drugs to treat disorders such as Huntington's

disease, traumatic brain injury or cancer.

The scientists began this project as a result of a separate study in

which they were screening 147,000 compounds to see which could

stimulate stem cells cultivated from rodent embryos to become heart

cells. Unexpectedly, five molecules stimulated the cells to transform

into forms resembling nerve cells. The researchers then created a

variation of these molecules, a new compound called Isx-9 (for

isoxazole-9). Isx-9 was easier to use than its initially discovered

relatives because it worked at a much lower concentration and also

dissolved more easily in water.

" It was completely serendipitous that we uncovered this neurogenic

[nerve-creating] small molecule, " Dr. Hsieh said. " I think it's one

of the most powerful neurogenic small molecules on the planet. In

theory, this molecule could provoke full maturation, to the point

that the new nerve cells could fire, generating the electrical

signals needed for full functioning. "

Nerve stem cells live in scattered groups in various areas of the

brain. They are capable of becoming several different types of cells,

not all of which are nerve cells.

In the study, rodent nerve stem cells from an area of the brain

called the hippocampus were cultured with Isx-9. They clustered

together and developed spiky appendages called neurites, which

typically happens when nerve cells are grown in culture.

Isx-9 also prevented the stem cells from developing into non-nerve

cells and was more potent than other neurogenic substances in

stimulating nerve-cell development. The molecule generated two to

three times more nerve cells than other commonly used compounds.

Neuroscientists believed for decades that the adult mammalian brain

could not grow new nerve cells. Instead, they thought, learning and

memory were strictly a matter of the brain making new connections

between existing cells.

It is now known, however, that the brain constantly creates new nerve

cells. In the hippocampus, which is involved with learning and

memory, stem cells mature into full-blown nerve cells at a rate of

thousands a day, Dr. Hsieh said.

Scientists know that when a mature nerve cell sends a chemical signal

called a neurotransmitter to a stem cell, the immature cell begins to

mature, but they don't know what biochemical pathways or genes are

involved, Dr. Hsieh said.

" The big gap in our knowledge is how to control these stem cells, "

she said.

Isx-9 appeared to act like a neurotransmitter-like signal on the

nerve stem cells, the researchers found. By culturing the stem cells

with the compound, the scientists identified a possible biochemical

pathway by which stem cells begin to become nerve cells.

The researchers next plan to test Isx-9 on a large number of

different combinations of RNA, the chemical cousin of DNA, to see on

which genes the compound might be working. They have also applied for

a patent on Isx-9 and its relatives.

Other UT Southwestern researchers involved in the study were Dr. Jay

Schneider, assistant professor of internal medicine; Dr. Zhengliang

Gao, postdoctoral researcher in molecular biology; Dr. Shijie Li,

postdoctoral researcher in molecular genetics; Midhat Farooqi, a

student in the Medical Scientist Training Program; Dr. Tie-Shan Tang,

instructor of physiology; Dr. Ilya Bezprozvanny, professor of

physiology; and Dr. Frantz, assistant professor of

biochemistry.

The work was supported by the Haberecht Wild-Hare Idea Program, the

W. Reynolds Foundation, the National Institute of Neurological

Disorders and Stroke, the Ellison Medical Foundation, the Welch

Foundation and the UT Southwestern President's Research Council.