Discovery of a pathway that regulates heart muscle regeneration
Research led by Dylan Burnette, associate professor of cell and developmental biology, and first-author Abigail Neininger, a graduate student in the Burnette lab, identified the Hippo pathway as a key regulator of heart muscle cell division, which has large translational implications for treatments after a heart attack. Their article was published on September 7 in Scientific Reports. This research was done in collaboration with Qi Liu, associate professor of biomedical informatics and biostatistics.
We sat down with Abigail Neininger to learn more about this exciting research.
What issue/problem does your research address?
Heart muscle cells, or cardiac myocytes, are the essential beating cells of the heart which generate the force necessary to pump blood throughout the body. However, these cells are non-proliferative, meaning that they do not divide and regenerate after an injury (for example, a heart attack). This leads to permanent cell death and heart damage. Thus, there is a concerted effort in the cardiovascular field to identify regulators of cardiac myocyte regeneration with the ultimate goal of inducing these cells to divide after injury.
What was unique about your approach to the research? Was anything about the work unique to Vanderbilt University?
In this study, we utilize human induced pluripotent stem cell-derived cardiac myocytes as a model system, as these cells have a comparable transcriptome to the immature cardiac myocytes which divide during heart development in vivo.
What were your findings?
We identified the Hippo pathway as a regulator of density-dependent cardiac myocyte division and showed that two small molecules that target the Hippo pathway can increase division of cardiac myocytes. The Hippo pathway is a kinase cascade which, when “on”, inhibits cell division. We found that this pathway was downregulated in sparsely-plated cells compared to dense monolayers (that is, cells which have fewer neighbors divide more, and this phenomenon is regulated in part by the Hippo pathway).
What do you hope will be achieved with the research results in the short and long terms?
We hope that these findings will open a conversation of the role of cell density in proliferation after a heart attack. In the infarct zone (the area of dying cardiac myocytes), cell density is reduced and there is a slight increase in markers of cell cycling. Past studies have been focused on finding regulators of global cardiac myocyte division rather than identifying regulators which only increase division at the infarct zone (such as the two small molecule inhibitors used in our study).
What are the societal/environmental/economic benefits of this research?
Approximately 800,000 heart attacks occur in the United States each year. Inducing heart tissue to regenerate has not been adopted in the clinic as there are several limits to these techniques which require several years of research to work through. We hope that by opening a conversation into the efficacy of regeneration as a tool and the dependence on cell density of these techniques, researchers can continue to expand treatment options for heart attack patients.
Where is this research taking you next? What will you personally be doing, or how will other researchers build on this work?
Our next studies are on adapting the techniques and model system used in this manuscript to identify further regulators of cardiac myocyte proliferation, and to also delve deeper into heart attack biology. Several other cell types are involved in heart attacks and scar formation/revision which also must be investigated in these contexts. In order for compounds like these to reach the clinic, several more lines of investigation must be opened into the best methods of treatment and patient safety.
This work was supported by the National Institutes of Health (MIRA R35 GM125028 to D.T.B.) and Vanderbilt University School of Medicine Program in Developmental Biology (Training grant T32-HD007502 to A.C.N.).
The article “The Hippo pathway regulates density‑dependent proliferation of iPSC‑derived cardiac myocytes” was published in Scientific Reports on September 7.