An important choreographer of the complicated dance of signals, enzymes and proteins that takes embryonic stem cells through the steps to becoming a beating heart muscle cell is the gene Sox17, said researchers from Baylor College of Medicine in a report in the current issue of the Proceedings of the National Academy of Sciences.
To be precise, Sox17 is critical in transforming primitive mesoderm (an early layer of tissue in the embryo) into the more specialized cardiac mesoderm from which heart muscle develops, said Dr. Michael Schneider, senior researcher of the report.
"Heart muscle formation by embryonic stem cells is a complex, multi-step process," said Schneider, professor of medicine, molecular and cellular biology, and molecular physiology and biophysics at Baylor College of Medicine. "We have succeeded in uncoupling the formation of cardiac mesoderm from its antecedent steps. That discovery provides immediate insight into how one might seek to generate cardiac muscle more effectively from embryonic stem cells."
"One of the major challenges is the very meager ability of the heart muscle to restore itself after cell death," said Schneider. Heart muscle cells die acutely during heart attacks and sporadically in chronic heart failure.
"Identifying stem cells that can be encouraged along the path to becoming heart muscle is a paramount scientific goal," he said.
Embryonic stem cells are a potential source because they have the potential of becoming every type of cell in the body. However, much research remains before scientists can outline a blueprint for how these totally undifferentiated cells can be guided to the "fate" of becoming heart muscle selectively.
Schneider and his colleagues used proteins that block certain signals for cell specialization at the surface of mouse embryonic stem cells to pinpoint early steps that lead to the development of heart muscle. Then, using "gene chip" technology to measure the expression of 40,000 mouse genes simultaneously, Schneider and his colleagues identified the sudden expression of Sox17 as a potentially important step for the signals that lead to heart formation.
Using a technique called RNA interference, they then blocked the action of Sox17 in the embryonic stem cells. By doing so, they prevented the embryonic cells from becoming cardiac muscle, almost completely.
"Knocking down Sox17 (reducing expression of the gene) had a dramatic effect, both on genes for structural components of the heart and also genes for transcription factors that turn on the cardiac fate," said Schneider.
Others who took part in the research include: Drs. Yu Liu, Masanori Asakura, Hironori Inoue, Teruya Nakamura, Motoaki Sano and Zhiyv Niu of BCM, Michelle Chen of Agilent Technologies in Santa Clara, California; and Robert J. Schwartz of the Institute of Biosciences and Technology at Texas A&M University Health Science Center in Houston.
Funding for this work came from the National Institutes of Health, the M. D. Anderson Foundation Chair, and the Fondation Leducq Transatlantic Network of Excellence for Cardiovascular Research.
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