Molecule prompts blood stem cells to help repair heart damage in animal model

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"The clinical potential is enormous," said Dr. Jay Schneider, assistant professor of internal medicine and senior author of the study, which appears online this week and in a future issue of the Proceedings of the National Academy of Sciences.

Despite medical advances in treating and preventing heart attacks, once the heart is damaged it cannot repair itself, said Dr. Schneider, a cardiologist.

"Heart attack is a man-made problem," he said. "It's a function of increased longevity and atherosclerosis, which have occurred at no other time in human evolution."

In the first stage of the current study, which involved mouse stem cells, the researchers screened some 147,000 compounds in UT Southwestern's Small Molecule Library to see which ones would activate genes known to be at work in the early stages of heart development.

This initial screening sifted out about 1,600 compounds, but the researchers narrowed their focus to a related group of molecules, among the most potent and easy to make, called Shz for sulfonyl-hydrazone.

The researchers then tested the effects of one Shz compound, Shz-3, a molecular variant synthesized by chemists at UT Southwestern, on human blood stem cells. These cells, called PBMCs for peripheral blood mononuclear cells, were cultured with Shz-3 for three days, then for seven days without the drug.

Tests showed that the Shz-treated cells began to create RNAs and proteins found only in heart cells. They were then implanted into the hearts of rats with heart damage. After a week, the function of the rats' hearts had significantly improved, and after three weeks, the organs contracted as strongly as they did before the damage. Tests showed that the human cells were alive and had incorporated themselves into the heart tissue, although the researchers could not tell whether the human cells had become fully functional, contracting heart cells.

"This functional test is a good first step," Dr. Schneider said "What this shows is that this drug can act on blood stem cells that are already being used in other clinical trials. This may speed its movement into clinical trials for heart repair."

Shz compounds do not appear to be toxic in mice, and because the human blood stem cells are washed for seven days after treatment, the compounds are likely not to be harmful to humans, although further tests are needed, Dr. Schneider said.

Further studies will examine precisely what the Shz drugs are doing to the cells, and to identify additional chemical signals that might drive the cells toward a more mature form of heart cell, the researchers said.

Other UT Southwestern researchers in internal medicine involved in the study were lead author Dr. Hesham Sadek, instructor; Britta Hannack, research assistant; Dr. Elizabeth Choe and Dr. Jessica Wang, former residents; Dr. Shuaib Latif, former cardiology fellow; Dr. Mary Garry, former assistant professor; Dr. Daniel Garry, former associate professor; Jamie Longgood, senior research associate in biochemistry; Dr. Douglas Frantz, assistant professor of biochemistry; Dr. Eric Olson, chairman of molecular biology; and Dr. Jenny Hsieh, assistant professor of molecular biology.

The work was supported by the Donald W. Reynolds Foundation, the Esther A. and Joseph Klingenstein Fund, the Ellison Medical Foundation, the Texas Higher Education Coordinating Board, the Welch Foundation and the Haberecht Wild-Hare Idea Program.

The University of Texas Southwestern Medical Center