Study finds two protein pathways that are downregulated in postnatal heart

Researchers uncovered two signalling channels in human hearts that are downregulated after birth.

Heart disease is one of the major causes of mortality globally, in part because the mature human cardiac lacks heart stem cells, which allow it to recover after injury. Induced pluripotent stem cells, which are undifferentiated human stem cells produced from adult cells, often skin tissue, may be coaxed to develop into cardiac myocytes in vitro, although they preferentially produce immature versions of these cells. This produces fetal-type cells rather than postnatal cardiomyocytes.

The difficulty to create mature cardiomyocytes has hampered the development of cell therapy for heart illness as well as cell creation for in vitro cardiac physiology and toxicity research. “Research to make human cardiac myocytes from pluripotent stem cells has exploded in the last decade,” said Bayardo Garay, a graduate student in the Medical Scientist Training Program. “Our research contributes to these efforts by demonstrating a feasible method for producing cells relevant to human illness.”

The researchers explored previously published genetic data on cardiomyocytes at various stages of development to uncover these two pathways.

Maturation in Heart Cells

“It is challenging to accomplish maturation of stem cell-derived somatic cells in a dish, but it is crucial for the production of human in vitro models of health and disease,” said Brenda Ogle, PhD, Professor and Head of the Department of Biomedical Engineering and Director of the Stem Cell Institute. “This research skillfully uses current data to find novel pathways that influence cardiomyocyte development and can be readily altered using small compounds to expedite cardiomyocyte maturation.”

The researchers conclude that inhibiting the MAPK and PI3K-AKT pathways on in vitro-derived human cardiomyocytes for only five days results in increased maturity in a variety of domains.

“This multidisciplinary work is the fruit of the university’s investment in collaborative science,” says Rita Perlingeiro, PhD, of the Cardiology Division/Department of Medicine, “and brings the cells we can produce in the lab significantly closer to being clinically relevant to cardiac disease in humans.”

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The National Institutes of Health and the American Heart Association provided funding for the investigation. Seed funding was also provided by the University of Minnesota Lillehei Heart Institute and the Institute for Engineering in Medicine Group Grant. The University of Minnesota University Imaging Centers also contributed resources and personnel to the project.

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