For years, pediatric cardiologists have been trying to understand the origin of a puzzling structural defect of the heart muscle wall, a congenital problem called left ventricular non-compaction(LVNC). In people with this defect, the muscle of the hearts biggest pumping chamber looks spongy rather than smooth and solid.

For such congenital cardiomyopathies, currently there is no effective therapy, and the only cure is heart transplantation, said StanfordsJoseph Wu, MD, PhD, a cardiologist who led a new study of the condition that published online this week inNature Cell Biology.

His team was looking for a new way to address a very old research problem: They didnt know how much they could trust studies done on animal models of the disease. Mouse and rat models of LVNC also have spongy heart muscle, but its not clear if their defect starts the same way as in humans, nor whether findings from rodent studies could help treat humans.

So Wus team used innovative stem cell techniques instead. They took skin and blood cells donated by four members of a family affected by LVNC and converted them into induced pluripotent stem cells, which are stem cells made in a lab from adult cells. Using these stem cells, the researchers then made human heart muscle cells that they could study in a dish. That gave them a way to study what was happening in patients hearts without taking heart muscle biopsies.

Before starting their work, the researchers already knew that LVNC begins long before birth, when the heart muscle fails to make an important developmental shift. In the earliest stages of cardiac development, its normal for the muscle to be spongy. At about 8 weeks of gestation, the human heart muscle is supposed to compress into a thick, compact mass, but that shift doesnt happen correctly in LVNC patients. Earlier studies gave conflicting information about why: maybe the heart muscle cells were proliferating too little, or maybe too much.

Another mystery about the disease is its range of severity, which varies from no symptoms at all to complete heart failure. As the new paper describes, the family who agreed to have their cells studied is a good example. Of three siblings who donated cells for research, one had already had a heart transplant, while the other two had hearts that pumped normally in spite of deeper trabeculations (the scientific word for the spongy formations). Meanwhile, their father had an enlarged heart, but no sponginess in his heart muscle and no other symptoms.

Using the heart muscle cells derived from all four people, the researchers identified the gene defect that causes LVNC in this family; it codes for a cardiac transcription factor or a protein that controls the expression of other genes called TBX20. The scientists conducted several experiments to figure out how the TBX20 abnormality changes heart muscle cell proliferation with the abnormality, the cells dont proliferate enough, it turns out. They also explored the exact signaling pathways that cause the problem, showing that the magnitude of signaling abnormalities could explain differences in symptom severity between family members. They created a mouse model with the familys gene defect for further characterization, and also showed that blocking the faulty signal from the altered TBX20 could restore the mutated cells ability to proliferate. Its possible that some day, they might be able to turn these findings into a drug that could correct heart muscle formation in affected fetuses before birth.

The new findings still leave unanswered questions about the origins of LVNC. Cardiologists suspect the problem can arise in several ways, and theyll need to study many more families to find out if TBX20 mutations are a common or rare cause. But the paper does demonstrate how induced pluripotent stem cells can overcome a research hurdle, and suggests that the same methods could help scientists tackling other hard-to-study conditions.

This study shows the feasibility of modeling such developmental defects using human tissue-specific cells, rather than relying on animal cells or animal models, Wu said. It opens up an exciting new avenue for research into congenital heart disease that could help literally the youngest in utero patients.

Previously: One of the most promising minds of his generation: Joseph Wu takes stem cells to heart, Stem cells create faithful replicas of native tissue, according to Stanford study and A cheaper, faster way to find genetic defects in heart patients Photo by amanda tipton

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