Affiliation:
1. Department of Pathology and Laboratory Medicine College of Medicine University of Cincinnati OH
2. Department of Molecular and Cellular Physiology College of Medicine University of Cincinnati OH
3. BioIntel Research Laboratory Department of Chemical and Petroleum Engineering Bioengineering Graduate Program School of Engineering University of Kansas Lawrence KS
4. Department of Internal Medicine Heart, Lung and Vascular Institute University of Cincinnati OH
Abstract
Background
Myocardial infarction results in a large‐scale cardiomyocyte loss and heart failure due to subsequent pathological remodeling. Whereas zebrafish and neonatal mice have evident cardiomyocyte expansion following injury, adult mammalian cardiomyocytes are principally nonproliferative. Despite historical presumptions of stem cell–mediated cardiac regeneration, numerous recent studies using advanced lineage‐tracing methods demonstrated that the only source of cardiomyocyte renewal originates from the extant myocardium; thus, the augmented proliferation of preexisting adult cardiomyocytes remains a leading therapeutic approach toward cardiac regeneration. In the present study we investigate the significance of suppressing cell cycle inhibitors
Rb1
and
Meis2
to promote adult cardiomyocyte reentry to the cell cycle.
Methods and Results
In vitro experiments with small interfering
RNA
–mediated simultaneous knockdown of
Rb1
and
Meis2
in both adult rat cardiomyocytes, isolated from 12‐week‐old Fischer rats, and human induced pluripotent stem cell–derived cardiomyocytes showed a significant increase in cell number, a decrease in cell size, and an increase in mononucleated cardiomyocytes. In vivo, a hydrogel‐based delivery method for small interfering
RNA
–mediated silencing of
Rb1
and
Meis2
is utilized following myocardial infarction. Immunofluorescent imaging analysis revealed a significant increase in proliferation markers 5‐ethynyl‐2′‐deoxyuridine,
PH
3,
KI
67, and Aurora B in adult cardiomyocytes as well as improved cell survivability with the additional benefit of enhanced peri‐infarct angiogenesis. Together, this intervention resulted in a reduced infarct size and improved cardiac function post–myocardial infarction.
Conclusions
Silencing of senescence‐inducing pathways in adult cardiomyocytes via inhibition of
Rb1
and
Meis2
results in marked cardiomyocyte proliferation and increased protection of cardiac function in the setting of ischemic injury.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
47 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献