Adult cardiomyocyte proliferation and heart regeneration
It is generally thought that the adult mammalian heart is almost completely incapable of regeneration. Adult heart injury and cardiomyocyte death therefore result in declining heart function that often progresses to heart failure. Heart failure is the leading cause of death in the U.S. The view that the adult heart is incapable of efficient regeneration stands in contrast to the observation that the embryonic mammalian heart is both proliferative and fully regenerative. This led us to consider how our understanding of embryonic cardiomyocyte proliferation might be extrapolated to the adult heart.
In ongoing work that has not yet been published, we have challenged the paradigm that the adult heart is incapable of significant regeneration. We advance the novel hypothesis that the degree of regenerative capacity is a variable trait subject to the influence of multiple polymorphic genes that vary in expression or function, such that different individuals will have more or less regenerative capacity dependent on their individual genetic backgrounds.
To validate these principles, we are using the Hybrid Mouse Diversity Panel (HMDP), a large collection of common inbred mouse strains and multiple panels of recombinant inbred mouse strains. Indeed, we found significant variability across these different mouse strains in the percentage of adult cardiomyocytes that are capable of proliferation. Mouse strains with more of these cardiomyocytes had a substantially greater degree of recovery of heart function with decreased scarring following heart injury (see the figure).
The true power of the HMDP is in being able to identify the genes responsible for trait variation via genome-wide association. We have already defined a number of chromosomal loci that influence heart regenerative capacity, and are in the process of identifying the specific genes and their polymorphisms that contribute to phenotype variation, and defining the molecular roles played by these genes in normal heart biology and in post-injury regeneration.
Variability in heart regenerative competence based on genetic background, and the genes and mechanisms we identify in mice that influence this variation, are likely to be shared in humans. We expect these to be appropriate targets for the development of new treatments to improve heart regeneration in all patients regardless of their genetic compositions.