Cardiomyocytes are the contractile cells of the heart muscle and they carry the pump work of the heart. Loss of cardiomyocytes, for example after a large myocardial infarction, is not adequately replaced, resulting in heart failure. Our laboratory studies the cellular and molecular mechanisms of cardiomyocyte proliferation, with special emphasis on answering several important biological questions. How do cardiomyocytes enter proliferative quiescence after differentiation? Are some differentiated cardiomyocytes capable of reentering the cell cycle? If cell cycle reentry is possible, how can this process be controlled? Inducing cardiomyocyte proliferation may provide an innovative strategy to enhance the regenerative capacity of mammalian hearts. The long-term objective of our research is to provide novel approaches and molecular targets to enhance the regenerative potential of human hearts.
Regeneration is an important mechanism of tissue homeostasis in multicellular organisms, and the heart's limited ability to regenerate spontaneously is remarkable. Many adult mammalian tissues, such as blood and skin, regenerate after injury, relying on undifferentiated stem cells. Heart tissue, like other tissues with limited regenerative capacity, is largely comprised of terminally differentiated cells. However, some cardiomyocytes in the adult heart undergo DNA synthesis and karyokinesis (nuclear division). For example, cardiomyocyte cell cycle activity in the region bordering a myocardial infarction increases transiently. Although this increase is not sufficient for effective regeneration, it suggests that some cardiomyocytes have the potential to proliferate in response to extracellular signals present in the infarct border zone. We are exploring how to promote cardiomyocyte cell cycle entry and division by applying specific factors.
We have discovered that a peptide of periostin, a component of the extracellular matrix, and neuregulin 1 a growth factor, induce cell cycle re-entry and division in differentiated cardiomyocytes. After experimentally inducing myocardial infarctions, we have shown that the application of recombinant periostin peptide or neuregulin 1, enhance cardiomyocyte cycling, reduce infarct size, and improve myocardial function. Thus inducing cardiomyocyte proliferation with periostin peptide or with neuregulin 1 shows great potential for repairing the mammalian heart after injury.
About Bernhard Kühn
Bernhard Kühn received an MD from Freie Universität Berlin and completed a internship residency in pediatrics at Yale-New Haven Children's Hospital and a fellowship in pediatric cardiology at Boston Children's Hospital. He was awarded the American College of Cardiology's Young Investigator Award (First Prize) in 2007.