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Stem Cells Used to Create Cells to Study Heart Condition

Posted Jun 21 2010 11:25am

Researchers have made stem cell lines from patients with LEOPARD syndrome, a rare developmental disorder. The accomplishment is a major step toward using stem cells to model disease pathways and test potential treatments.

Image of enlarged heart cells with organized red fibers.
Heart cells derived from LEOPARD syndrome iPS cells. Heart muscle fibers are stained red. Image courtesy of Carvajal-Vergara et al, Nature.

Scientists recently made great progress in learning how to create induced pluripotent stem (iPS) cells. The cells are made by genetically altering adult cells to take on the characteristics of embryonic stem cells. iPS cells can grow indefinitely in the laboratory and can theoretically change, or differentiate, into all cell types found in the body.

Researchers have been working to harness the potential of iPS cells to repair tissues and organs. The unique advantage of iPS cells is that scientists could potentially create them from cells taken from individuals with particular diseases or conditions. Studying the cells as they differentiate and develop could shed light on the molecular mechanisms of disease.

A team of researchers led by Drs. Ihor R. Lemischka and Bruce D. Gelb at Mount Sinai School of Medicine set out to create iPS cells from patients with LEOPARD syndrome. The rare disorder is characterized by dark skin markings, deafness and other developmental problems. Hypertrophic cardiomyopathy, a thickening of the heart muscle, affects about 80% of children with the syndrome and is its most dangerous symptom.

About 90% of LEOPARD syndrome cases are caused by mutations in the PTPN11 gene, which encodes a protein called tyrosine phosphatase SHP2. PTPN11 is expressed throughout the body and is essential for normal development, making it difficult for researchers to understand what goes wrong during development in people with the disorder. The effort to develop stem cells for the study of LEOPARD syndrome was funded by NIH’s National Institute of General Medical Sciences (NIGMS) and others.

In the June 9, 2010, issue of Nature, the researchers reported that they used 4 genes to reprogram skin cells from 2 patients with LEOPARD syndrome. The new cell lines could successfully differentiate into several different cell types. The researchers then coaxed the iPS cells to become heart cells and found that they were enlarged and had other characteristics of hypertrophic cardiomyopathy.

The researchers analyzed protein extracts from the iPS-derived heart cells and identified several potential targets for future study. The reprogrammed cells had alterations in various cell signaling pathways, some previously linked with cardiac hypertrophy.

"We knew there was potential in using pluripotent stem cells from people with genetic disorders to develop diseases in vitro, but our study is the first to successfully create abnormal heart cells," Lemischka says.

These cell lines may help researchers identify compounds that can reverse the characteristics of LEOPARD syndrome. "Now that we have developed these cells, we can study why they become enlarged and develop treatments to prevent them from overgrowing," Lemischka says.

—by Harrison Wein, Ph.D.

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