London: Researchers have discovered a unique genetic switch that guides stem cells so they develop into specialised heart muscle.
The findings could help identify the underlying causes of heart defects in congenital heart diseases and may lead to new ways of controlling stem cells in the laboratory to grow cellular repair kits for patients with damaged hearts. The research team found a protein known as Mel18 is responsible for regulating a piece of cellular machinery that applies temporary silencers to the DNA in developing cells. This protein is normally active in a group of embryonic stem cells in the mesoderm – a layer in the embryo that develops into all the muscles and red blood cells in the body. By acting on a protein complex known as PRC1 – a member of the Polycomb family of protein complexes that remodel the structure of chromosomes – it is able to silence certain genes.
This sets the developing cells off down a pathway that sees them differentiate into specialized heart muscle cells. However, the researchers found Mel18 also serves another unexpected function by turning on particular genes as the cardiac cells begin to develop in the mesoderm. Together this dual functionality appears to result in the growth of healthy heart tissue. “Mel18 is highly expressed in embryonic stem cells. During differentiation its expression goes down, while those of its brothers goes up,” said Luciano Di Croce, an epigeneticist at theCentre for Genomic Regulation in Spain.
“Interestingly this occurs in a cell-specific manner, which means each brother seems to be responsible for the differentiation of a set of cell types,” said Di Croce. “Mel18 remains high in cardiac cells, while it is not really expressed in neuronal cell precursors, for example. “Although we have not looked in to it with great detail, it is likely that mis-expression of Mel18 in cardiac cells might be responsible for heart defects or pathologies,” said Di Croce. The research team used a series of experiments on stem cells in culture in the laboratory, along with genetic sequencing techniques, to determine that Mel18 binds to key genes and regulates their transcription.
Mesoderm cells with depleted levels of Mel18 were also found to be blocked from developing as functioning heart muscle cells and few were capable of beating. This suggests deficiencies in Mel18 may be involved in causing certain cardiac problems where the heart muscle develops abnormally, according to Dr Lluis Morey, who was the lead author of the study at the Centre for Genomic Regulation. However, previous studies in mice have shown that animals with mutations in the gene for Mel18 develop apparently normal hearts yet die shortly after birth. “This needs to be investigated further. It could be that some of Mel18’s brothers can compensate for Mel18 deficiency during early development,” said Di Croce. The study was published in the journal Cell Stem Cell.
