Medical Research

Mayo Clinic

Jan van Deursen, Darren baker, Atta Behfar, Hu Li, Andre Terzic
Rochester, MN
$1,200,000
June 2017

Humans and mice have the innate capacity to regenerate heart tissue, but the proliferative capacity of cardiomyocytes dramatically declines after birth, which is a key barrier to the use of regenerative medicine in the treatment of various heart diseases.  In contrast, lower vertebrates retain cardiac regenerative ability throughout life, which has spurred interest into the underlying molecular and cellular mechanisms with the intent to exploit the insights gained to reestablish cardiac homeostasis and repair in humans.  In zebrafish, the three layers that surround the myocardium, referred to as the pericardium, have been identified as a source of cells and signaling factors critical for cardiac regeneration.  A multidisciplinary team of Mayo Clinic investigators discovered that, in adult mice, senescent cells accumulate in the pericardium with aging and that the systemic elimination of senescent cells from midlife on attenuates fundamental aspects of cardiac aging, including cardiomyocyte hypertrophy, loss of stress tolerance and diastolic dysfunction, all of which are linked to heart failure.  These findings provide a rare, unexpected and promising entry point for closing the longstanding knowledge gap about the mechanisms that limit cardiac maintenance and repair as humans and mice age.  The investigators will exploit this opportunity by combining innovative mouse models and cell culture methods with advanced systems biology to identify pericardial signaling pathways that act to sustain myocardial architectural integrity and function.  They will also determine how bioactive factors secreted from pericardial senescent cells that accumulate with aging perturb these signaling networks.  Lastly, the team will evaluate the role of senescent cells in cardiac loss of function and regeneration in mice subjected to myocardial infarction.

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