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Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury: Role of Human CD34+ Cells Deficient in MicroRNA-377.

Abstract：

BACKGROUND:MicroRNA (miR) dysregulation in the myocardium has been implicated in cardiac remodeling after injury or stress. OBJECTIVES:The aim of this study was to explore the role of miR in human CD34(+) cell (hCD34(+)) dysfunction in vivo after transplantation into the myocardium under ischemia-reperfusion (I-R) conditions. METHODS:In response to inflammatory stimuli, the miR array profile of endothelial progenitor cells was analyzed using a polymerase chain reaction-based miR microarray. miR-377 expression was assessed in myocardial tissue from human patients with heart failure (HF). We investigated the effect of miR-377 inhibition on an hCD34(+) cell angiogenic proteome profile in vitro and on cardiac repair and function after I-R injury in immunodeficient mice. RESULTS:The miR array data from endothelial progenitor cells in response to inflammatory stimuli indicated changes in numerous miR, with a robust decrease in the levels of miR-377. Human cardiac biopsies from patients with HF showed significant increases in miR-377 expression compared with nonfailing control hearts. The proteome profile of hCD34(+) cells transfected with miR-377 mimics showed significant decrease in the levels of proangiogenic proteins versus nonspecific control-transfected cells. We also validated that serine/threonine kinase 35 is a target of miR-377 using a dual luciferase reporter assay. In a mouse model of myocardial I-R, intramyocardial transplantation of miR-377 silenced hCD34(+) cells in immunodeficient mice, promoting neovascularization (at 28 days, post-I-R) and lower interstitial fibrosis, leading to improved left ventricular function. CONCLUSIONS:These findings indicate that HF increased miR-377 expression in the myocardium, which is detrimental to stem cell function, and transplantation of miR-377 knockdown hCD34(+) cells into ischemic myocardium promoted their angiogenic ability, attenuating left ventricular remodeling and cardiac fibrosis.

journal_name

J Am Coll Cardiol

journal_title

Journal of the American College of Cardiology

authors

Joladarashi D,Garikipati VNS,Thandavarayan RA,Verma SK,Mackie AR,Khan M,Gumpert AM,Bhimaraj A,Youker KA,Uribe C,Suresh Babu S,Jeyabal P,Kishore R,Krishnamurthy P

doi

10.1016/j.jacc.2015.09.009

subject

Has Abstract

pub_date

2015-11-17 00:00:00

pages

2214-2226

issue

eissn

0735-1097

issn

1558-3597

pii

S0735-1097(15)06147-1

journal_volume

pub_type

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Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury: Role of Human CD34+ Cells Deficient in MicroRNA-377.