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J Am Coll Cardiol. 2015 Nov 17;66(20):2214-2226. doi: 10.1016/j.jacc.2015.09.009.

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

Author information

1
Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas.
2
Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania.
3
Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, Illinois.
4
Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas.
5
Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas; Department of Cell and Developmental Biology, Department of Cardiothoracic Surgery, Weill Cornell Medical College, New York, New York. Electronic address: pkrishnamurthy@houstonmethodist.org.

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.

KEYWORDS:

endothelial progenitor cells; heart failure; neovascularization

PMID:
26564600
PMCID:
PMC4644493
DOI:
10.1016/j.jacc.2015.09.009
[Indexed for MEDLINE]
Free PMC Article

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