Interview with Ellen Dirkx: winner of the FCVB Young Investigators Awards

Myocardial infarction (MI) causes cell death and triggers hypertrophic remodeling of surviving cardiomyocytes, resulting in heart failure. A therapeutic approach aiming at inducing cardiomyocyte proliferation while inhibiting the hypertrophic response would improve cardiac function and prevent MI-induced heart failure.

By bioinformatics analyses, she and her group identified the miR-106b~25 cluster, containing miR-106b, miR-93 and miR25, to potentially target a network of negative cell cycle regulators, as well as series of pro-hypertrophic factors. Based on these findings, they hypothesized that over-expression of the miR-106b~25 cluster would recover the heart muscle after MI by stimulating cardiomyocyte proliferation and inhibiting hypertrophy. 

They observed that in vivo overexpression of miR-106b~25 using adeno-associated virus 9 (AAV9) in neonatal mice induced cardiomyocyte proliferation (indicated by an increased incorporation of EdU into cardiomyocytes, combined with increased levels of the proliferative markers Aurora-B and phosho-histone 3), while cardiomyocyte size was not affected.

In line with this observation, in adult mice, AAV9-miR106b~25 treatment increased heart mass without inducing hypertrophy. To test the regenerative potential of myocyte proliferation secondary to AAV9-miR-106b~25 gene transfer, mice were randomized to receive a control AAV9-MCS (empty vector) or AAV9-miR-106b~25 and sham surgery or myocardial infarction (MI). Echocardiographic measurements reported an improvement of cardiac function after MI upon AAV9-miR106b~25 treatment versus AAV9-MCS, which was associated with a reduced infarction size and a clear decrease in fibrotic damage.

In summary, this data demonstrates that AAV9-miR106b~25 treatment reduces scar formation and improves cardiac function after MI by stimulating cardiomyocyte proliferation and inhibiting hypertrophic remodelling. These findings might give rise to a new regenerative approach aiming at healing the cardiac muscle after myocardial injury.