Growing heart cells and insulin producing cells

SINCE THE isolation of human embryonic stem cells three years ago, scientists have been excited about the prospect of using these cells to produce all the different types of tissues in our body, such as heart tissue to repair damaged hearts.

Now researchers at the Technion-Israel Institute of Technology have for the first time succeeded in growing the precursors of heart cells from human embryonic stems cells. This puts the researchers considerably closer to clinical application in humans.

The research, conducted by Dr. Lior Gepstein of the Faculty of Medicine at the Technion-Israel Institute of Technology and Dr. Joseph Itskovitz-Eldor of the Faculty of Medicine and Rambam Medical Center, is published in the Journal of Clinical Investigation.

In a second study, another team of researchers at the Technion- Israel Institute of Technology demonstrated that human embryonic stem cells can produce insulin, a result that could signal an important step toward a cure for type 1 diabetes.

Their research, led by Dr. Karl Skorecki of the Faculty of Medicine at the Technion-Israel Institute of Technology, is published in the August Diabetes.

Type 1 diabetes is a disease that generally results from the autoimmune destruction of pancreatic islet cells, which produce the insulin that "unlocks" the cells of the body allowing glucose to enter and fuel them.

The only way to cure the disease is by pancreas transplantation. However, due to the shortage of organ donations and other factors, there remains a greatly insufficient supply of organs. The study "offers the promise that," said Dr. Christopher D. Saudek, president of the American Diabetes Association.While other researchers recently reported on the use of stem cells from bone marrow to repair mouse hearts, Drs. Gepstein and Itskovitz- Eldor's research is a step forward in two important ways.

"Embryonic stem cells have advantages over stem cells derived from adult tissues," Dr. Gepstein points out. "They can proliferate far more than can stem cells from adults, producing far more descendant cells.

This is important, because many millions of cells are needed to repair organs. In addition, we know that embryonic stem cells can differentiate into all the tissues of the body, while a given type of adult stem cell seems to differentiate into only a small set of tissue types."

As a result, the techniques that the Israel Institute of Technology group has developed could be modified to produce other types of human tissue. The group began with a line of cells derived from the earliest embryonic stem cell work.

After growing an undifferentiated mass of cells by a now-standard technique, the team shifted the cells into a special growth suspension, with growth factors that the team had optimized to produce differentiated growth.

As they divided, the stem cells aggregated into microscopic clumps called embryoid bodies.

In about 10% of the embryoid bodies, the researchers found small groups of cells that were spontaneously contracting, just as do the cells that develop into heart tissue in an embryo.

The researchers isolated the clumps, each consisting of twenty to thirty thousand cells, to test whether they were indeed early- stage cardiomyocytes and thus destined to differentiate into heart cells.

Based on further extensive tests, they are convinced that the cells are cardiomyocytes, the cells that differentiate into heart cells.

"We used a number of different tests to determine if these were really cardiomyocytes," explains Gepstein. "We compared the genes that are turned on or activated in these cells with the genes in known cardiomyocytes.

We looked at the proteins in the cells, and the cells' electrical activity as they regularly contracted.

We also looked at the cells' structure under an electron microscope and at their chemical activity, such as their uptake of calcium.

Finally, we looked at how these cells respond to hormones like adrenaline, which causes heart muscles to contract faster."

The cells passed all the tests with flying colors, demonstrating that they are indeed early-stage cardiomyocytes. It seems likely that if placed in an adult human heart, these cells would produce mature human heart muscle cells, Gepstein says. The next step in moving towards clinical applications, such as injecting cardiomyocytes into damaged human hearts, is to significantly increase the number of cells produced.

To do this, the Technion-Israel Institute of Technology team is experimenting with different combinations of growth factors that will induce the stem cells to produce pure cultures of only cardiomyocytes.

This will both greatly increase the number of cells towards the several million needed for heart repairs, and eliminate the delicate and laborious task of identifying and separating out the cardiomyocyte clumps from the other cells

"Patients with end-stage heart failure are often dependent on the availability of heart donors," notes Prof. Rafael Beyar, dean of the Faculty of Medicine at the Technion-Israel Institute of Technology.

"This new research may lead to breakthrough interventional tools to treat this devastating disease."

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