Targeting Progenitors to Reverse Chronic Heart Scars
Abstract
Topic Area: Cardiovascular Health The human heart possesses a poor ability to regenerate heart muscle after a heart attack and heals itself by scar formation. Lost heart muscle is replaced by scar tissue that does not contribute to the pumping ability of the heart, increases hemodynamic burden on the remaining viable heart muscle, and ultimately leads to the development of heart failure. However, unlike many other tissues such as the liver or skin, where scar tissue can be resorbed, in the heart, scar tissue once formed persists for the lifetime of the individual. Chronic persistent scarring in the heart induces deleterious structural and functional changes in the heart that directly contribute to the development of heart failure. Approximately 600,000 patients are annually diagnosed with heart failure in the United States, and the amount of scar tissue independently predicts their mortality and prognosis. Despite the importance of chronic scaring in the heart and other organs after acute injury, there is currently no therapy to reverse or reduce the volume of chronic scar tissue. Little is known about the biological reasons underlying the persistence of scars chronically in the heart long after the injury has abated. In this proposal, we present a fresh approach to this long unanswered biological question about the mechanisms of chronic scar persistence in tissues. Most tissues in the body (e.g., skin, blood) are renewed throughout the lifetime of the individual by progenitor or stem cells that give rise to daughter cells that in turn generate cells of the tissue. In this regard, scar tissue can be thought of as a micro-environment within an organ where scar-forming cells must renew themselves to secrete proteins (primarily collagens) that maintain the volume of the scar. Yet, little is known about how chronic scars in the heart or other organs replenish themselves. Here, we present a novel hypothesis about scar replenishment and propose that analogous to mechanisms of renewal of normal tissues, there exists a population of progenitor cells in chronic scar tissue that renew scar-forming cells in scar tissue and maintain scar. We further hypothesize that if such cellular mechanisms of scar replenishment are targeted, then scar replenishment will decrease over time and should lead to reduction in the volume of chronic scar. Reduction in chronic scar burden should improve the compliance and functioning of cardiac chambers and overall lead to better heart function and reduce scar-related complications such as arrhythmias. The knowledge obtained from this research will provide fresh biological insight into an age-old question in wound healing about the mechanisms contributing to persistence of scars. Moreover, our proposal, by determining the effects of targeting cellular replenishment on chronic scar burden, potentially provides a novel therapeutic strategy to decrease scar burden. Our experiments, if successful in reducing scar burden, could help ameliorate heart failure and scar-related complications in millions of patients who suffer from this disease. Moreover, the principles discovered in this study could be applicable to the treatment of scar tissue in other organs as well.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610491
Entities
People
- Arjun Deb
Organizations
- United States Army
- University of California, Los Angeles