Mechanically-induced Signaling Directs Cardiac Maturation and Aging
12:30 – 1:30pm, Foege N130A (Wallace H. Coulter Seminar Room)
Adam J Engler, PhD, University of California, San Diego, Sanford Consortium for Regenerative Medicine
Cells respond to the stiffness of their surrounding niche, but stiffness is highly dynamic from the onset of fertilization through senescence. As matrix is secreted and assembled by cardiac fibroblasts during development, the myocardium stiffens 10-fold. Dynamic stiffening helps instruct stem cells to specify and then mature into cardiomyocytes with robust sarcomeres. While this response is well known to be myosin-dependent, we have identified a novel role for the AKT/GSK3b pathway in regulating chicken cardiomyocytes’ response to dynamic stiffening from screens of mechanosensitive kinases. While these proteins may change activity in the presence of softer or stiffer niche, what has also not been clear has been what converts signals from biophysical to biochemical stimuli that the cell can interpret. In the context of aging, junctional proteins appear to play critical roles in transmitting forces and preserving cardiac function. Using Drosophila melanogaster, we have also explored the role of one such protein, vinculin, in age-associated diastolic dysfunction. Expression and localization changes with age perturb the cytoskeleton to ultimately adversely affect heart relaxation and impair chamber filling; overexpression or knockdown have further elucidated a protective role for the junctions in maintaining fractional shortening and wall velocities with time. In the context of these examples, I will also illustrate how our findings have influenced the translation of cell-based therapies or the identification of novel therapeutic targets.
Adam J. Engler is a professor of Bioengineering at UC San Diego and is affiliated with the Material Science and Biomedical Sciences Programs. He also is a resident scientist at the Sanford Consortium for Regenerative Medicine. His research focuses on how physical properties of the niche influence stem cell function and misregulate muscle function and heart performance during disease and aging. Dr. Engler earned his B.S.E. degree in bioengineering and a Ph.D. in mechanical engineering and applied mechanics at the University of Pennsylvania in the lab of Dr. Dennis Discher. Dr. Engler then moved to Princeton University’s Department of Molecular Biology as a Postdoctoral Research Fellow in the lab of Dr. Jean Schwarzbauer where his work was funded by the National Cancer Institute. Dr. Engler is the 2008 recipient of the Rupert Timpl and Rita Schaffer Young Investigator Awards from the International Society for Matrix Biology and the Biomedical Engineering Society, respectively. He is also a 2009 NIH Innovator Award recipient, a 2010 Young Investigator Awardee from the Human Frontier Science Program, and a 2013 IDEA Awardee from the Dept. of Defense.