Gladstone scientists identify key factors in heart cell creation

April 26, 2009

Scientists at the Gladstone Institute of Cardiovascular Disease have identified for the first time key genetic factors that drive the process of generating new heart cells. The discovery, reported in the current issue of the journal Nature, provides important new directions on how stem cells may be used to repair damaged hearts.

For decades, scientists were unable to identify a single factor that could turn nonmuscle cells into beating heart cells. Using a clever approach, the research team led by Benoit Bruneau, Ph.D., found that a combination of three genes could do the trick. This is the first time any combination of factors has been found to activate cardiac differentiation in mammalian cells or tissues.

"The heart has very little regenerative capacity after it has been damaged," said Dr. Bruneau. "With heart disease the leading cause of death in the Western world, this is a significant first step in understanding how we might create new cells to repair a damaged heart."

Two of the three genes encode proteins called transcription factors, which are master regulators that bind to DNA and determine which genes get activated or shut off. The two transcription factors, GATA4 and TBX5, cause human heart disease when mutated and also cooperate with each other to control other genes. When Dr. Bruneau and postdoctoral fellow Jun K. Takeuchi added different combinations of transcription factors to mouse cells, these two seemed important for pushing cells into heart cells--but they were not enough.

"When we finally identified the key factor that could work with GATA4 and TBX5 to turn cells into beating heart cells, it was somewhat of a surprise to us," said Dr. Bruneau.

The surprising factor was a cardiac-specific protein called BAF60c, which helps determine whether transcription factors like GATA4 and TBX5 can even gain access to the DNA regions they were supposed to turn on or off. "Our previous studies had shown that chromatin remodeling complexes were important," said Dr. Bruneau. "Mice with lower levels of these complexes have severe heart defects and defective cardiac differentiation. These observations prompted us to look at Baf60c in heart differentiation."

The effect was dramatic. Addition of the three factors directed differentiation of mouse mesoderm, which normally has the potential to make bone, blood, muscle, heart, and other tissues, specifically into cardiac muscle cells (cardiomyocytes) that beat rhythmically, just like normal heart cells. In fact, even cells that normally contribute to the placenta could be induced to transform into beating cardiomyocytes.

"Together, these factors give us a potent mechanism to control cellular differentiation," said Dr. Bruneau. "This knowledge may help us to understand how to reprogram new cardiomyocytes for therapeutic purposes."
-end-
The research was supported by the Human Frontiers Science Program, MEXT, Mitsubishi Foundation, the National Institutes of Health, and William H. Younger, Jr.

About the Gladstone Institutes

The J. David Gladstone Institutes, an independent, nonprofit biomedical research organization, affiliated with the University of California, San Francisco, is dedicated to the health and welfare of humankind through research into the causes and prevention of some of the world's most devastating diseases. Gladstone is comprised of the Gladstone Institute of Cardiovascular Disease, the Gladstone Institute of Virology and Immunology and the Gladstone Institute of Neurological Disease. More information can be found at www.gladstone.ucsf.edu.

Gladstone Institutes

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.