Research in the Del E. Webb Neuroscience, Aging and Stem Cell Research Center is attacking the problem of heart disease on two fronts. Investigators are employing strategies based on cell and molecular biology to stave off the death of heart cells and to develop replacement cells that can rebuild damaged organs. This two-pronged approach can be thought of as: "Protecting what you have and replacing what you've lost."
On the protection front, Professor Rolf Bodmer and Assistant Professor Giovanni Paternostro are using genetics to examine how hearts age. It has been known for many years that the ability of a heart to adapt to stress and recover decreases with age, but the underlying biology is not well understood. Bodmer and Paternostro use a simple organism, the fruit fly, which has been studied by geneticists for a century, to identify the genes that control the aging process.
In flies, just as in humans, aged hearts do not withstand stress as well as younger hearts. Paternostro has found mutant flies whose hearts appear perennially robust. He and his colleagues are currently working to isolate and examine the genes that cause these mutations. Bodmer and his team are studying a number of genes that are believed to cause heart defects in humans born with Downs syndrome, a birth defect caused by the presence of an extra copy of chromosome 21. These genes have “cousins” in flies, and Bodmer’s group has found that several of them do affect heart function. Bodmer’s group has also identified genes in flies that cause their hearts to age prematurely or, conversely, to remain young relative to the age of the fly. Many of these genes are also found in humans, and a number of them are associated with congenital heart malformations. By manipulating some of the genes they have found, Bodmer’s laboratory can cause hearts to age more slowly than normal. Their hope is that drugs or genetic therapies can be devised, based on their work, that will help to delay or treat heart failure in humans.
Other Burnham scientists are working on strategies to replace heart tissue damaged by disease. These strategies employ stem cells, relatively immature cells that can be directed to become different types of specialized cells, including, it is hoped, cardiac muscle cells, known as cardiomyocytes. These newly-derived heart cells would then be grafted to fill the lesions created by cardiac disease.
Professor Mark Mercola has identified a number of genes that guide initial formation of the heart in developing embryos. His laboratory has applied this knowledge to induce mouse embryonic tissue and embryonic stem cells to take on heart-like properties. For instance, a dish of cultured cells will beat in unison, much like the rhythmic beating displayed by a functioning heart. Their work indicates that it should be possible to develop protocols to induce stem cells to differentiate into functioning cardiac cells.
Cardiomyocytes derived from embryonic stem cells can be cultured in the same dish with genuine cardiac muscle cells, and in fact, some will "pair up" with the mature cells and take on heart-like appearance and function. Mercola and his team have shown that problems develop, however, with these stem cell-derived “heart” cells. The cells appear normal for a time, but then undergo hypertrophy, similar to the enlarged heart cells seen in people with heart failure. Although the cells appear normal alone, contact with normal functioning cardiomyocytes triggers their abnormal growth.
In collaboration with Assistant Professor Vincent Chen, Mercola’s group is examining how the stem cells in these cultures are communicating with their mature cardiomyocyte neighbors. Cardiac cells are "electrically coupled," and exchange signals that allow them to beat in harmony. Chen’s expertise in measuring electrical activity in cells and the communication between them is allowing the team to characterize the electrical behavior of the differentiated stem cells and compare it to that of normal mature cardiomyocytes. The results of this work should constitute a basis for developing methods to normalize electrical activity in differentiated stem cells.
Mercola’s laboratory is also collaborating with a team of chemists to develop candidate drugs to combat the hypertrophy seen in heart-like stem cells. He and his colleagues have identified one chemical compound that appears to block this trend in the stem cells co-cultured with mature heart cells. Now, the team will use their knowledge of the signaling that triggers the stem cells’ abnormal growth to develop drugs that are particularly suited to block the abnormal growth. They are also pursuing other potential compounds that may lead to new agents to protect against enlarged hearts in patients with chronic heart disease.
When engineering heart tissue from stem cells, however, scientists will need to be careful not to halt their proliferation too soon. Otherwise, they will not obtain sufficient tissue to transplant. If the cells mature too soon, they stop dividing; if they do not mature and keep dividing too long, they risk displaying the hypertrophy described above. Therefore, a balance needs to be achieved between cell division and maturation.
One way to control that balance is to replicate the mechanisms the developing embryo uses to ensure it has enough cells to build heart muscle. Mercola’s group is studying a number of genes that control cell proliferation during embryonic heart development. One of these is called Notch, which prevents heart cells from reaching a point at which they can no longer divide. Their long-term goal is to develop protocols, using a combination of genetic and drug-based approaches, that will balance division and maturation appropriately in differentiating stem cells. Such protocols should result in a population of healthy, mature cardiac cells that can be transplanted into patients suffering from heart disease.
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