Advances in understanding of cardiac-specific genes in heart development

Researchers at the Texas Heart Institute at St. Luke's Episcopal Hospital (THI at St. Luke's) announced today the results of research which they believe marks a significant advance in understanding how cardiac-specific genes are turned on during the development of the heart in mice embryos.

“Being able to better select the right stem cells for the job, we certainly will be able to improve treatments for patients with acute and chronic heart disease and heart failure.”

Doctors anticipate that the findings could lead to a better way to differentiate human stem cells that can be placed into damaged human hearts and spur regeneration of heart muscle and other tissues.

THI doctors and scientists are already conducting clinical trials in which improved heart functions have been demonstrated in patients who have been injected with their own bone marrow-derived stem cells after severe heart failure. However, the process by which the cells affect these repairs remains elusive. Revealing the exact mechanism should enable physicians and researchers to refine and optimize stem cell treatment. This research puts them a step closer.

"This is a major insight into how heart development is regulated," says Dr. Edward T. H. Yeh, head of the research team and the Janice and Robert McNair Foundation Scholar at THI. Dr. Yeh is also chair of the Cardiology Department at The University of Texas-M.D. Anderson Cancer Center.

The results of the study are being published this week in the scientific journal, Molecular Cell.

Dr. Yeh and his colleagues found that a protein modifier chemical known as SUMO regulates the transcription of two genes - Gata4 and Gata6 - during embryonic development. These genes are essential to healthy heart development and transcription is part of the process that allows them to do their work.

The research shows that a SUMO-specific protease (an enzyme that effects proteins in cells) known as SENP-2 is a master switch turning on the Gata4 and Gata6 genes to allow them to perform their heart-development work. Dr. Yeh discovered SUMO and a set of enzymes that remove SUMO called the SENPs more than 10 years ago. SUMO and SENP are now known to play important roles in heart development, neurological diseases and cancer.

Dr. Yeh's group discovered that SENP-2 regulates a key protein called PC2 that uses SUMO to alter proteins within cells and turn off gene transcription. During early development, SUMO-modified PC2 binds to the suppressive code of these proteins to turn off many genes that are required for development of the heart and other organs. SENP-2 switches off this suppressive code to allow the heart to develop normally.

By more fully understanding how these genes, proteins and the protein code interact, doctors believe they will be better able to target and differentiate stem cells to help repair damaged hearts. They will be better able to select cells that are more efficient in the healing process.

This builds on the work of researchers at THI at St. Luke's who already have found that stem cells derived from a patient's own bone marrow can be transplanted into a damaged heart, where they can lead to the development of new heart muscle and blood vessels. THI was the first to receive U.S. Food and Drug Administration approval for human trials of this therapy and is one of only five centers in the country in the Cardiovascular Cell Therapy Research Network, the first national consortium to receive federal funding for adult stem cell studies. The findings of Dr. Yeh's team are expected to significantly advance this work.

"This is a terribly important and very insightful advance," said Dr. James T. Willerson, president and medical director for THI and a pioneer in the field of gene therapy for treating heart failure. "Being able to better select the right stem cells for the job, we certainly will be able to improve treatments for patients with acute and chronic heart disease and heart failure."

The findings are not limited to hearts but would also apply in the development of other organs, says Dr. Yeh.