The heart is arguably the hardest working muscle in the human body and without its incessant, regular beating the body’s organs would be starved of life-giving nutrients. Yet how the heart grows from a thin layer of cells in the embryo into a powerful and symbolic organ has remained largely unknown. Now, a study from researchers at the Centre for Genomic Regulation (CRG) has identified a unique genetic switch, controlled by the protein Mel18, that appears to guide stem cells so they develop into specialised heart muscle. The team state that the findings could help to reveal the underlying causes of heart defects in congenital heart diseases, and new ways of growing cellular repair kits for patients with damaged hearts. The opensource study is published in the journal Cell Stem Cell.
Previous studies show that the Mel18 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 seems to set the developing cells off down a pathway that sees them differentiate into specialised heart muscle cells. Mel18 is highly expressed in embryonic stem cells. During differentiation its expression goes down, while those of its brothers goes up. 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.
Earlier studies show that Mel18 remains high in cardiac cells, while it is not really expressed in neuronal cell precursors, for example. The team state that although they 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. The current study 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.
The current study 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. Results show that 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. The lab state that this suggests deficiencies in Mel18 may be involved in causing certain cardiac problems where the heart muscle develops abnormally. They go on to stress that previous studies in mice have shown that animals with mutations in the gene for Mel18 develop apparently normal hearts yet die shortly after birth. The group conclude that this needs to be investigated further using Mel18’s brothers to compensate for Mel18 deficiency during early development.
The team surmise that harnessing Mel18 promises to make it easier to grow functioning heart cells in the laboratory from induced pluripotent stem cells, or iPS cells. They go on to add that these avoid the use of embryos by reverting adult cells back to a more embryo-like state and are seen as a rich source of cells for research or clinical use in treating patients. For the future, the researchers state their findings provide a novel way to ‘reconvert’ human iPS into cardiac cells.