Combinatorial miRNA1a/15b interference drives adult cardiac regeneration
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
BACKGROUND
Despite its promise, cardiac regenerative therapy remains clinically elusive due to the difficulty of spatio-temporal control of proliferative induction, and the need to coordinately reprogram multiple regulatory pathways to overcome the strict post-mitotic state of human adult cardiomyocytes. The present study was designed to identify a novel combinatorial miRNA therapy to address this unmet therapeutic need.
METHODS
We performed a combinatorial miRNA interference screen specifically targeting cardiac-predominant miRNAs regulating key aspects of cardiomyocyte mitotic induction to cell-cycle completion, including sarcomerogenesis, metabolic and cell-cycle control pathways. Cardiomyocyte proliferation and cardiac function were assessed in human cardiac biopsies, human cardiac tissue mimetics and in mouse disease models.
RESULTS
We identified combinatorial interference of miR-1a and miR-15b (LNA-1a/15b) as drivers of adult cardiomyocyte proliferation. Due to miR-1a/15b function on multiple processes modulating adult cardiomyocyte mitosis, its inhibition augmented adult cardiomyocyte cell-cycle completion and daughter cell formation, and improved contractility in in vitro 2D and 3D ischemic models, and in a mouse model of ST-segment elevation myocardial infarction (STEMI). Due to the cardiac-restricted pattern of miR-1a/15b expression, this strategy provides a feasible strategy for specific cardiomyocyte proliferative induction with minimal risk of neoplasm formation and off-target toxicity.
CONCLUSIONS
Combinatorial miR-1a/15b inhibition drives mitotic re-entry in adult cardiomyocytes and improves cardiac function in response to myocardial infarction. Our data provides a novel and clinically feasible LNA-based anti-miR-1a/15b strategy to attenuate heart failure and highlights an underutilized therapeutic strategy for simultaneous co-regulation of multiple disease pathways through combinatorial miRNA interference.
