Weeks after the discovery that heart cells regenerate themselves under their own steam – albeit very slowly – another scientific study paper reports on how to make heart cells in the laboratory.
The paper, published in the April 26 online edition of Nature, defines the three factors that make up the "minimal input" necessary to turn embryonic stem cells into beating heart muscle cells, senior author Benoit Bruneau told Medical Device Daily's sister publication, BioWorld Today.
The three factors have different roles: two of them, GATA4 and TBX5, are cardiac-specific transcription factors, while the third, BAF60c, is a chromatin remodeling factor that also is cardiac-specific. By transfecting embryos with the three factors, Bruneau and first author Jun Takeuchi could induce embryonic cells to differentiate into cardiomyocytes, or cardiac muscle cells.
Chromatin remodeling factors act to make genes more or less accessible to the transcription machinery by changing the structure of histones – structural elements that keep DNA wound up in the cell. In the combination of BAF60c, GATA4, and TBX5, BAF60c apparently enables GATA4 to access DNA and initiate the transcription of genes that are critical for heart cells to develop.
The idea that chromatin remodeling factors can be tissue-specific, Bruneau said, is itself a fairly new idea. Such factors are currently conceptualized as "general helpers" – partly because they were first discovered in yeast, which is a unicellular organism, but also because "biochemists often don't think in terms of organs and organisms," but in terms of more general pathways instead.
On the basic science front, Bruneau and his colleagues plan to study the cellular pathways that lead from the three factors to cardiac myocytes in greater detail. Clinically, there is of course the hope that it might be possible to culture cardiac cells for transplantation. While heart disease is now the leading cause of death in the Western world, such transplantation would have a large pool of potential beneficiaries. Though a recent study has demonstrated that the adult heart can and does make new cells, at a rate of one to two percent of cells a year, the heart's regenerative capacity is not sufficient for the heart to repair itself after injury.
A source of such cardiac cells could enable better results for cell transplants; to date, such transplants – using bone marrow cells – has brought little if any improvement in heart failure patients, and what improvement there is does not stem from new cardiomyocytes. Likewise, another recent paper also reports that heart repair can be induced by the developmental protein thymosin beta-4, but its effects also do not depend on new cardiac muscle cells; instead, thymosin beta-4 appears to stimulate new blood vessel growth.
Transplanting a mix of cells that is enriched for cardiomyocytes has been more promising in preclinical studies, but even the enriched mixture, Bruneau said, contained only about 50 percent heart muscle cells, whereas "our approach may allow the differentiation of pure cardiac myocytes."
In combination, the three factors were able to make cardiac cells not only from anterior mesoderm, which is a natural progenitor for cardiac muscle cells, but also from posterior mesoderm and precurors, which are not. Bruneau said that this ability to get cardiac cells from cells that do not normally produce them bodes well for the possibility of ultimately producing clinically useful cell populations with the three factors.
"We think that because this set of factors was so powerful, we should be able to harness these factors in an adult cell of some sort" to produce cardiac myocytes. Bruneau's team is not, however, limiting itself to one cell type; they are currently testing the factors in iPS cells, adult and embryonic stem cells.