Inhibition of let-7c Regulates Cardiac Regeneration after Cryoinjury in Adult Zebrafish.

Suneeta Narumanchi,Heikki Ruskoaho,Hong Wang,Ilkka Tikkanen,Katariina Immonen,Karri Kalervo,Mika Laine,Sanni Perttunen,Päivi Lakkisto,Jere Paavola,Riikka Kosonen

doi:10.3390/jcdd6020016

Abstract

The let-7c family of micro-RNAs (miRNAs) is expressed during embryonic development and plays an important role in cell differentiation. We have investigated the role of let-7c in heart regeneration after injury in adult zebrafish. let-7c antagomir or scramble injections were given at one day after cryoinjury (1 dpi). Tissue samples were collected at 7 dpi, 14 dpi and 28 dpi and cardiac function was assessed before cryoinjury, 1 dpi, 7 dpi, 14 dpi and 28 dpi. Inhibition of let-7c increased the rate of fibrinolysis, increased the number of proliferating cell nuclear antigen (PCNA) positive cardiomyocytes at 7 dpi and increased the expression of the epicardial marker raldh2 at 7 dpi. Additionally, cardiac function measured with echocardiography recovered slightly more rapidly after inhibition of let-7c. These results reveal a beneficial role of let-7c inhibition in adult zebrafish heart regeneration.

Highlights

Cardiovascular diseases are the leading cause of death globally [1]
Our study reveals that inhibition of let-7c results in an increased rate of fibrinolysis, increased number of proliferating cardiomyocytes, higher expression of the epicardial cell marker raldh2 and a faster rate of improvement of cardiac function
We found a single injection of let-7c antagomir to result in let-7c silencing in the cryoinjured fish in all organs tested; the heart, the liver, and the kidney

Summary

Introduction

Cardiac remodeling after myocardial infarction in mammals leads to scar formation and hypertrophy [2,3]. Cell-lineage-tracing studies with zebrafish have shown complete regeneration after amputation through proliferation of pre-existing cardiomyocytes [9,10,11,12], unlike in mammals [3]. Cryoinjury more closely mimics the physiological responses associated with myocardial infarction, including cell death, inflammation and scarring [4,5,17]. Cell death and inflammation in the infarct area is followed by simultaneous proliferation of endocardium, epicardium and cardiomyocytes [4,5]. The adult zebrafish heart completely regenerates and scar tissue is replaced by functional cardiac tissue, in approximately two months following cryoinjury [11]

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