Scientists at the Gladstone Institute of Cardiovascular Disease have identified three genetic factors that drive the process of generating new heart cells. The study appearing in Nature and carried out with mouse cells is reportedly 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,” points out Benoit Bruneau, Ph.D. “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 GATA4 and TBX5. Both are known to cause heart disease in humans when mutated and to 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 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,” remarks 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,” Dr. Bruneau explains. “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.”
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 normal cardiac muscle cells. In fact, even cells that normally contribute to the placenta could be induced to transform into beating cardiomyocytes.